KR102050712B1 - Inhibitors of influenza viruses replication - Google Patents

Abstract

A method of inhibiting replication of influenza virus in a biological sample or patient, the amount of influenza virus in a biological sample or patient, comprising administering to a biological sample or patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof And a method for treating influenza in a patient, wherein the meaning of formula (I) is described herein. There is provided a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof, wherein the meaning of formula (IA) is described herein. There is provided a pharmaceutical composition comprising an effective amount of said compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Description

Inhibitors of influenza viruses replication

Representative Case Number: VPI / 09-103 WO

This application claims the priority of US Provisional Application No. 61 / 87,713, filed June 17, 2009 and US Provisional Application No. 61 / 287,781, filed December 18, 2009. The full teachings of these applications are incorporated herein by reference.

Influenza spreads worldwide in the prevalent season, killing hundreds of thousands of people every year-millions of people in pandemic years. For example, three influenza pandemics occurred in the 20th century, killing tens of millions of people, all of which were caused by the emergence of new strains of the virus in the human body. Often, these new strains result from the spread of existing influenza viruses in humans from other animal species.

Influenza is mainly transmitted from person to person through large virus-loaded droplets that occur when an infected person coughs or sneezes; These large droplets can then settle on the mucosal surface of the upper respiratory tract of sensitive individuals around the infected person (eg, within about 6 feet). It can also be spread by direct or indirect contact with airway secretions, such as touching the eye, nose or mouth after touching a surface contaminated with influenza virus. Adults can spread influenza to others about a day before the symptoms begin, about five days after the onset of symptoms. Children and people with weakened immune systems can get sick for more than 10 days after symptoms develop.

Influenza virus is an RNA virus of the family Orthomyxoviridae , which includes five genera, Influenza Virus A, Influenza Virus B, Influenza Virus C, Isavirus and Togoto virus. Include.

The genus Influenza A has one species, the influenza A virus. Wild waterfowl are natural hosts for various influenza A. Occasionally, the virus can spread to other species and then cause fatal infections in poultry or cause human influenza pandemic. Type A virus is the most malignant human pathogen of the three influenza types and causes the most serious disease. Influenza A viruses can be classified into different serotypes based on antibodies that respond to these viruses. The serotypes identified in humans are H1N1 (causing Spanish influenza in 1918), H2N2 (causing Asian influenza in 1955), H3N2 (causing Hong Kong flu in 1968), and H5N1 (in order of known pandemic deaths). Pandemic threat in the influenza season of 2007-08), H7N7 (with the potential for abnormal zoogenic infections), H1N2 (patient in humans and pigs), H9N2, H7N2, H7N3 and H10N7.

Influenza Virus B genus has one species, the influenza B virus. Influenza B infects humans almost exclusively and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. Influenza of this type variates at rates two to three times slower than type A, and as a result is less genetically diverse, having only one influenza B serotype. As a result of this lack of antigenic diversity, some immunity against influenza B is usually obtained at a young age. However, since influenza B is sufficiently mutated, persistent immunity is not possible. This reduced rate of antigenic change, along with its limited host range (inhibiting cross species antigenic shift), ensures that the pandemic of influenza B does not occur.

The influenza virus C genus has one species, the influenza C virus, which can infect humans and swine and cause serious diseases and local epidemics. Influenza C, however, is less common than other types and usually appears to cause mild disease in children.

Influenza A, B and C viruses are structurally very similar. Viral particles are 80-120 nm in diameter, and filamentary morphologies can occur but are usually spherical. Unusually for a virus, its genome is not a single piece of nucleic acid; Instead, it contains seven or eight pieces of fragmented negative-sense RNA. The influenza A genome contains 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2 (NEP), PA Encrypts PB1, PB1-F2 and PB2.

HA and NA are large glycoproteins on the outside of viral particles. HA is a lectin that mediates the binding of the virus to the target cell and the introduction of the viral genome into the target cell, whereas NA is responsible for the release of progeny virus from infected cells by cleaving sugars bound to mature viral particles. Get involved. Thus, these proteins have been the target of antiviral drugs. In addition, they are antigens capable of generating antibodies. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, for example, forming the criteria for distinguishing H from N in H5N1 (see above).

Influenza incurs indirect costs of preventive measures as well as the direct costs of lost productivity and associated medical treatment. In the United States, influenza incurs more than $ 10 billion a year in total costs, but future pandemics are estimated to generate hundreds of billions of dollars in direct and indirect costs. Preventive costs are also high. Governments have spent billions of dollars in the preparation and practice of a potential H5N1 avian influenza pandemic worldwide, and this cost is not just about buying drugs and vaccines, but also about developing disaster drills and improved border control strategies. Related.

Recent treatments for influenza include vaccination and chemotherapy or chemoprophylaxis with antiviral agents. Influenza vaccination with influenza vaccine is often recommended for high risk groups such as children and the elderly or people with asthma, diabetes or heart disease. However, you can still get influenza after vaccination. The vaccine is formulated again seasonally for a few specific influenza strains, but may not include all strains that actively infect humans worldwide in that season. It takes about six months for a manufacturer to formulate and produce the millions of doses needed to deal with seasonal pandemic; Occasionally, new or overlooked strains will protrude and people will be infected even if they have been vaccinated (in the case of H3N2 Fuji flu in the influenza season of 2003-2004). In addition, since the vaccine takes about two weeks to take effect, there is a possibility that the vaccine is infected with the strain to be prevented immediately before vaccination.

In addition, the effectiveness of these influenza vaccines is variable. Due to the high rate of mutation of the virus, certain influenza vaccines usually provide protection for only a few years. Since influenza viruses change rapidly over time and different strains predominate, vaccines formulated for one year may not be effective in the next year.

In addition, due to the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase of influenza vRNAs produces one nucleotide insertion error per approximately 10000 nucleotides, which is the approximate length of influenza vRNAs. Thus, almost all newly created influenza viruses are mutant-antigenic drift. The genome is separated into eight separate fragments of the vRNA, allowing for the mixing or gene reassortment of the vRNA if more than one virus family infects a single cell. The resulting rapid change in viral genetics results in antigenic mutations, allowing the virus to infect new host species and quickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, while neuraminidase inhibitors are particularly effective, but viruses can develop resistance to standard antiviral drugs.

Thus, there is still a need for drugs for treating influenza infections, such as drugs with extended treatment window and / or reduced sensitivity to viral titers.

Summary of the Invention

The present invention generally relates to methods of treating influenza, methods of inhibiting replication of influenza virus, methods of reducing the amount of influenza virus, compounds and compositions that can be used in the methods.

In one aspect, the invention relates to a method of inhibiting replication of influenza virus in a biological sample or patient. In one embodiment, the method comprises administering to said biological sample or patient an effective amount of a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof.

Formula IA

In Chemical Formula IA,

Z ¹ is -R ^* , -F, -Cl, -CN, -OR ^* , -CO ₂ R ^* , -NO ₂ or -CON (R ^* ) ₂ ;

Z ² is -R ^* , -OR ^* , -CO ₂ R ^* , -NR ^* ₂ or -CON (R ^* ) ₂ ;

Z ³ is —H, —OH, halogen (eg —Cl or —Br), —NH ₂ ; -NH (C ₁ -C ₄ alkyl); Independently from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -O (C ₁ -C ₄ alkyl), or substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl) C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected;

R ¹ is —H or C ₁ -C ₆ alkyl;

R ² is -H; -F; -NH ₂ ; -NH (C ₁ -C ₄ alkyl); -N (C ₁ -C ₄ alkyl) _2; -C = N-OH; Cyclopropyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH ₃ and -CH _{3 which} are substituents; Or a substituent of halogen, cyano, hydroxy, and -O (C ₁ -C ₄ alkyl) group independently selected from an optionally substituted C ₁ -C ₄ alkyl with at least one substituent selected from the consisting of a;

R ³ is —H, —Cl, —F, —OH, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl ) ₂ , -Br, -CN, or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ ,- Independently from the group consisting of OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₄ aliphatic optionally substituted with one or more substituents selected;

R ⁴ is

(여기서, 환 T는 하나 이상의 J^A로 임의로 치환된 C₃-C₁₀ 비-방향족 카보사이클, 또는 하나 이상의 J^B로 임의로 치환된 3원 내지 10원의 비-방향족 헤테로사이클이거나, 임의로, 환 T와 R⁹는 하나 이상의 J^A로 임의로 치환된 비-방향족 C₅-C₁₀ 카보사이클 또는 하나 이상의 J^B로 임의로 치환된 5원 내지 10원의 비-방향족 헤테로사이클을 형성한다);i)

Wherein ring T is a C ₃ -C ₁₀ non-aromatic carbocycle optionally substituted with one or more J ^A , or a 3-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B , or optionally, a ring T and R ⁹ forms a non-aromatic C ₅ -C ₁₀ carbocycle optionally substituted with one or more J ^A or a 5-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B );

(여기서, 환 J는 하나 이상의 J^B로 임의로 치환된 3원 내지 10원의 비-방향족 헤테로사이클이다); 또는ii)

Wherein ring J is a 3-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B ; or

(여기서, 환 D는 하나 이상의 J^D1로 임의로 치환된 4원 내지 10원의 비-방향족 헤테로사이클이다)이고;iii)

Wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ;

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo, -NCO and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B each, together with the atom (s) to which they are attached, form a 4-8 membered ring optionally substituted with one or more J ^E1 (eg, a spiro ring or a fused ring) Form independently;

Q ¹ is independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR ) NR-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-,- NRC (O) -, -NRC ( O) NR'-, -NRCO 2 -, -OC (O) NR'-, -S (O) -, -SO 2 -, -SO 2 NR'-, -NRSO _2- , -NRSO ₂ NR'-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or- (CR ⁶ R ⁷ ) _p -Y ^1- ;

Y ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR ) NR-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-,- NRC (O) -, -NRC ( O) NR'-, -NRCO 2 -, -OC (O) NR'-, -S (O) -, -SO 2 -, -SO 2 NR'-, -NRSO _2- , -NRSO ₂ NR'-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O- or -CO ₂ SO _2- ;

R ⁵ is i) -H; ii) a C ₁ -C ₆ aliphatic group optionally substituted with one or more J ^C1 ; iii) a C ₃ -C ₁₀ non-aromatic carbocycle or a 6 to 10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^C1 ; Or iv) a 4-10 membered non-aromatic heterocycle or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more J ^D1 ;

R ⁵ , together with Q ¹ , optionally forms a 4-8 membered non-aromatic ring optionally substituted with one or more J ^E1 ;

R ⁶ and R ⁷ are each independently —H or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from the group consisting of aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy, or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl;

R ⁹ is independently —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ Alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy , C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy or C ₂ -C ₆ alkoxyalkoxy;

R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _1- C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy ego;

Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl;

R and R 'are each independently -H or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ amino C ₁ -C ₆ alkyl independently substituted with one or more substituents optionally and independently selected from the group consisting of alkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Or; Optionally, R ', together with R ⁵ and the nitrogen atom to which they are attached, form a 5- to 7-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ;

R ^* is independently: i) -H; ii) substituents halogen, cyano, hydroxy, oxo, amino, carboxy, C ₃ -C ₈ non-aromatic carbocycle, 5- or 6-membered non-aromatic heterocycle, phenyl, 5- or 6-membered hetero A C ₁ -C ₆ alkyl group optionally substituted with one or more substituents independently selected from the group consisting of aryl, —O (C ₁ -C ₆ alkyl) and —C (O) (C ₁ -C ₆ -alkyl) , Wherein the alkyl groups in -O (C ₁ -C ₆ alkyl) and -C (O) (C ₁ -C ₆ -alkyl) are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO Optionally and independently substituted with one or more substituents independently selected from the group consisting of ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy; The carbocycle, heterocycle, phenyl and heteroaryl are each independently and optionally substituted with one or more J ^E1 ; Or iii) C ₃ -C ₈ non-aromatic carbocycles or 4- to 8-membered non-aromatic heterocycles each independently and optionally substituted with one or more J ^El ;

J ^C1 and J ^D1 are halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (= NR) R ^c , -C (= NR) NR ^b R ^c , -NRC (= NR) NR ^b R ^c , -C (O) OR ^b , -OC (O) R ^b ,- NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b , -NRSO ₂ NR ^c R ^b , -P (O ) (OR ^a ) ₂ , -OP (O) (OR ^a ) ₂ , -P (O) ₂ OR ^a and -CO ₂ SO ₂ R ^b are each independently selected from the group consisting of, or optionally, two J ^C1 And two J ^D1 , together with the atom (s) to which they are attached, independently form a 4-8 membered ring optionally substituted with one or more J ^E1 ;

J ^E1 are each independently halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl) and —C (O) (C ₁ -C ₆ -alkyl), wherein said alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C Optionally and independently substituted with one or more substituents independently selected from the group consisting of ₄ alkoxy;

R ^a is independently

i) halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O (C ₁ -C ₆ alkyl), -C (O) (C ₁ -C ₆ -alkyl), C ₃ -C ₈ One or more substituents independently selected from the group consisting of non-aromatic carbocycles, 4- to 8-membered non-aromatic heterocycles, 5- to 10-membered heteroaryl groups, and 6- to 10-membered carbocyclic aryl groups C ₁ -C ₆ aliphatic group optionally substituted with wherein the alkyl groups for the substituents of the C ₁ -C ₆ aliphatic group represented by R ^a are halogen, cyano, hydroxy, oxo, —NH, respectively. ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ Optionally and independently substituted with one or more substituents independently selected from the group consisting of H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy; The carbocycle, heterocycle, heteroaryl and carbocyclic aryl groups for the substituents of the C ₁ -C ₆ aliphatic group represented by R ^a are each, optionally and independently substituted with one or more J ^E1 ;

ii) C ₃ -C ₈ non-aromatic carbocycles or 4- to 8-membered non-aromatic heterocycles, each optionally and independently substituted with one or more J ^El ; or

iii) a 5-10 membered heteroaryl or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^El ;

R ^b and R ^c are each independently R ^a or -H; Optionally, R ^b and R ^c , together with the nitrogen atom (s) to which they are attached, each independently form a 5- to 7-membered non-aromatic heterocycle optionally substituted with one or more J ^E1 ;

p is independently 1, 2, 3 or 4;

t is 0, 1 or 2;

j is 1 or 2;

z is 1 or 2.

In another embodiment, the method comprises administering to said biological sample or patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Formula I

In Formula I,

R ¹ is -H;

R ² is —H, —CH ₃ , —NH ₂ , —NH (C ₁ -C ₄ alkyl) or —N (C ₁ -C ₄ alkyl) ₂ ;

R ⁴ is i) a C ₃ -C ₁₀ non-aromatic carbocycle optionally substituted with one or more J ^A ; ii) 4- to 10-membered non-aromatic heterocycle optionally substituted with one or more J ^B ; Or iii) J ^C ; C ₃ -C ₈ non-aromatic carbocycles or 6 to 10 membered carbocyclic aryl groups, each optionally and independently substituted with one or more J ^A ; And C ₁ optionally substituted with one or more substituents independently selected from the group consisting of a 5-10 membered heteroaryl group or a 4-10 membered non-aromatic heterocycle, each optionally and independently substituted with one or more J ^B. -C ₆ aliphatic group;

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo, -NCO and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B each independently form, together with the atom (s) to which they are attached, a five to seven membered ring optionally substituted with one or more J ^E1 ;

J ^C is halogen, cyano, oxo, -OR ⁵ , -SR ⁵ , -NR'R ⁵ , -C (O) R ⁵ , -CO ₂ R ⁵ , -OC (O) R ⁵ , -C (O ^{) NR'R 5, -C (O)} NRC (O) OR 5, -NRC (O) NRC (O) OR 5, -NRC (O) R 5, -NRC (O) NR'R 5, -NRCO ₂ R ⁵ , -OC (O) NR'R ⁵ , -S (O) R ⁵ , -SO ₂ R ⁵ , -SO ₂ NR'R ⁵ , -NRSO ₂ R ⁵ and -NRSO ₂ NR'R ⁵ Independently selected from the group consisting of;

Q ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO ₂ -, -OC (O) NR'-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO _2- , -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- ;

Y ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO ₂ -, -OC (O) NR'-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO ₂ -or -NRSO ₂ NR'-;

R ⁵ is i) -H; ii) a C ₁ -C ₆ aliphatic group optionally substituted with one or more J ^C1 ; iii) a C ₃ -C ₈ non-aromatic carbocycle or a 6 to 10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^C1 ; Or iv) a 4-8 membered non-aromatic heterocycle or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more J ^D1 ; R ⁵ together with Q ^{1 form} a 5- to 7-membered non-aromatic ring, optionally substituted with one or more J ^E1 ;

J ^C1 and J ^D1 are halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O ) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b Or -NRSO ₂ R ^b , -NRSO ₂ NR ^c R ^b and -P (O) (OR ^a ) _2- ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 ;

Z ¹ , Z ² , R ³ , R ⁶ , R ⁷ , R, R ', R ^* , J ^El , R ^a , R ^b , R ^c and p are each independently as described in Formula IA.

In another aspect, the invention relates to a method of reducing the amount of influenza virus in a biological sample or patient. The method comprises administering to said biological sample or patient an effective amount of a compound represented by formula (I) or formula (IA) as described above, respectively.

In another aspect, the present invention relates to a method of treating or preventing influenza in a patient, comprising administering to the patient an effective amount of a compound represented by Formula I or Formula IA, as previously described independently.

In another aspect, the invention relates to a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —H, C ₁ -C ₆ alkyl, —S (O) ₂ —R ″ or —C (O) OR ”; Alternatively, R ¹ is —H or C ₁ -C ₆ alkyl;

또는

이고; 여기서,R ⁴ is

or

ego; here,

Ring A is a C ₃ -C ₁₀ non-aromatic carbocycle optionally substituted with one or more J ^A , or a heterocycle optionally further substituted with one or more J ^B ;

Rings B and C are each independently a 4-10 membered non-aromatic heterocycle optionally and independently further substituted with one or more J ^B ;

Ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ;

Rings A and R ⁸ optionally form a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ⁹ optionally form a 5-10 membered non-aromatic bridged Form a carbocycle or heterocycle, or rings A and R ¹¹ optionally form a 5- to 10-membered non-aromatic bridged carbocycle or heterocycle, wherein the carbocycle is each optionally added to one or more J ^A Each heterocycle is optionally further substituted with one or more J ^B ;

Q ² is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR) NR-, -CO _2- , -OC (O)-, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC ( O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or -(CR ⁶ R ⁷ ) _p -Y ^1- ;

Q ³ is independently a bond, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR) NR-, -CO _2- , -C (O) NR-, -SO _{2- ,} -SO ₂ N (R)-, -C (O) NRC (O) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- ;

Is independently i) halogen, cyano, hydroxyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkoxy, One or more independently selected from the group consisting of C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ -alkyl optionally substituted with substituents, or ii) halogen, cyano, hydroxy, oxo, nitro, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ -hydroxyalkyl, C ₂ -C ₆ -alkoxyalkyl, C ₁ -C ₆ -aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ -hydroxyalkoxy And one or more substituents independently selected from the group consisting of C ₂ -C ₆ alkoxyalkoxy Substituted, C ₃ -C ₆ carbocyclic group, 5- or 6-membered heteroaryl group or phenyl group;

Z ¹ , Z ² , Z ³ , Q ¹ , Q ² , Q ³ , Y ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R, R ', R ^* , J ^A , J ^B , J ^C1 , J ^D1 , J ^E1 , R ^a , R ^b , R ^c and p each independently inhibit the replication of the influenza virus As described in Formula (IA) above for the method of inhibition;

n and m are each independently 0 or 1 when rings A and B are 3 to 6 members;

n and m are each independently 0, 1 or 2 when rings A and B are 7 to 10 members;

k is 0, 1 or 2;

x and y are each independently 0, 1 or 2;

z is 1 or 2;

Provided that when Y ¹ is a bond, R ⁵ is neither -H nor a C ₁ -C ₆ aliphatic group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is neither -H nor a C ₁ -C ₆ aliphatic group.

In another embodiment, the invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the meanings of the letters of formula (I) are as follows:

R ¹ is —H, C ₁ -C ₆ alkyl, —S (O) ₂ —R ″ or —C (O) OR ”; Alternatively, R ¹ is —H or C ₁ -C ₆ alkyl;

또는

이고; 여기서,R ⁴ is

or

ego; here,

Ring A is a C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^A , or a heterocycle optionally further substituted with one or more J ^B ;

Rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more J ^B ;

Ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ;

Is independently i) halogen, cyano, hydroxyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkoxy, One or more independently selected from the group consisting of C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ -alkyl optionally substituted with substituents, or ii) halogen, cyano, hydroxy, oxo, nitro, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ -hydroxyalkyl, C ₂ -C ₆ -alkoxyalkyl, C ₁ -C ₆ -aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ -hydroxyalkoxy And one or more substituents independently selected from the group consisting of C ₂ -C ₆ alkoxyalkoxy Substituted, C ₃ -C ₆ carbocyclic group, 5- or 6-membered heteroaryl group or phenyl group;

Z ¹ , Z ² , Q ¹ , Q ² , Q ³ , Y ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R, R ', R ^* , J ^C1 , J ^D1 , J ^E1 , R ^a , R ^b , R ^c and p are each independently represented in Formula I for a method of inhibiting replication of the influenza virus As described;

n and m are each independently 0 or 1 when rings A and B are 4 to 6 members;

n and m are each independently 0, 1 or 2 when rings A and B are 7 or 8 members;

k is 0, 1 or 2;

x and y are each independently 0, 1 or 2;

z is 1 or 2;

Provided that when Y ¹ is a bond, R ⁵ is neither -H nor an unsubstituted C ₁ -C ₆ aliphatic group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is neither -H nor a C ₁ -C ₆ aliphatic group.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound represented by formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein The meanings of the letters of the IA are each independently as described above for the compounds of the present invention.

The invention also provides the use of a compound described herein to inhibit replication of influenza virus in a biological sample or patient, reduce the amount of influenza virus in a biological sample or patient, or treat influenza in a patient. do.

Also described herein are compounds described herein for the preparation of a medicament for treating influenza in a patient, reducing the amount of influenza virus in a biological sample or patient, or inhibiting replication of influenza virus in a biological sample or patient. It also provides the use of.

FIG. 1 shows 5 days before oral gavage (10 ml / kg) of an initial dose of a compound of Formula 514 (100 mg / kg) or vehicle alone (0.5% methylcellulose / 0.5% Tween 80) 2 hours prior to infection It is a graph showing the survival rate of Balb / c mice (4-5 weeks old) over time for the prophylactic study lasted twice a day.
FIG. 2 shows Balb / c mice (4 to 4) for a therapeutic treatment study in which compound of Formula 588 (200 mg / kg) or vehicle alone was administered by oral gavage at 24 hours post infection and continued twice daily for 10 days. It is a graph showing the survival rate of 5 weeks of age) over time.
3A-8B are tables showing some specific compounds of the present invention.

Use of the compounds described

One aspect of the present invention is generally directed to inhibiting influenza virus replication in a biological sample or patient, reducing the amount of influenza virus in a biological sample or patient (reducing virus titer), and treating influenza in a patient. It relates to the use of pharmaceutically acceptable compositions comprising the compounds or pharmaceutically acceptable salts described herein, or the compounds or pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates generally to the use of the compounds represented by formula (I) or formula (IA) or pharmaceutically acceptable salts thereof for any of the uses specified above.

Formula IA

Formula I

The first set of letters of formula (I) and (IA) are independently as follows:

Z ¹ is -R ^* , -F, -Cl, -CN, -OR ^* , -CO ₂ R ^* , -NO ₂ or -CON (R ^* ) ₂ . Specifically, Z ¹ is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -F, -Cl, -CN, -CO ₂ H, -CO ₂ (C ₁ -C ₆ alkyl), -CONH ₂ , -CONH (C ₁ -C ₆ alkyl) or -CON (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups (eg C ₁ -C ₆ alkyl,- Alkyl groups represented by O (C ₁ -C ₆ alkyl), -CO ₂ (C ₁ -C ₆ alkyl), -CONH (C ₁ -C ₆ alkyl) and -CON (C ₁ -C ₆ alkyl) ₂ ) Are each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy substituted with one or more substituents independently selected from the group consisting of do. Specifically, Z ¹ is -H, -F, -Cl, C ₁ -C ₄ haloalkyl (eg -CF ₃ ), C ₁ -C ₄ alkyl, -CH ₂ NH ₂ , -C (O) NH ₂ , -C (O) NH (CH ₃ ), -C (O) N (CH ₃ ) ₂ , -O (C ₁ -C ₄ alkyl) or -CN. Specifically, Z ¹ is -H, -F, -Cl, -CF ₃ , C ₁ -C ₄ alkyl or -CN. Specifically, Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ or -CN. Specifically, Z ¹ is -H, -F or -CN. Specifically, Z ¹ is -H or -F.

Z ² is -R ^* , -OR ^* , -CO ₂ R ^* , -NR ^* ₂ or -CON (R ^* ) ₂ . Specifically, Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ , wherein said alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —NH (C ₁ -C ₆ alkyl), and —N (C ₁ Alkyl groups represented by -C ₆ alkyl) ₂ are each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy It is substituted with one or more substituents independently selected from the group consisting of. Specifically, Z ² is —H, C ₁ -C ₆ alkyl or —O (C ₁ -C ₆ alkyl), wherein said alkyl groups are each optionally and independently substituted. Specifically, Z ² is -H or optionally substituted C ₁ -C ₆ alkyl.

Z ³ in formula (IA) is —H, —OH, halogen, —NH ₂ ; -NH (C ₁ -C ₄ alkyl); Independently from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -O (C ₁ -C ₄ alkyl), or substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl) C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected. Specifically, Z ³ is independently selected from the group consisting of -H, -O (C ₁ -C ₄ alkyl), or substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl) C ₁ -C ₆ alkyl optionally substituted with the above substituents. Specifically, Z ³ is -H or C ₁ -C ₆ optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl) which are substituents. Alkyl. Specifically, Z ³ is -H.

R ¹ is —H or C _1-6 alkyl. Specifically, R ¹ is -H.

R ² is -H; -F; -NH ₂ ; -NH (C ₁ -C ₄ alkyl); -N (C ₁ -C ₄ alkyl) _2; -C = N-OH; Cyclopropyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH ₃ and -CH ₃ ; Or a substituent halogen, cyano, hydroxy, and -O (C ₁ -C ₄ alkyl) group independently selected from C ₁ -C ₄ alkyl optionally substituted with one or more substituents selected from the consisting of. Specifically, R ² is -H, -CH ₃ , -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ . Specifically, R ² is —H, —F, —CH ₃ , —CH ₂ OH, or —NH ₂ . Specifically, R ² is -H or -CH ₃ .

R ³ is —H, —Cl, —F, —OH, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl ) ₂ , -Br, -CN, or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ ,- Independently from the group consisting of OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₄ aliphatic optionally substituted with one or more substituents selected. Specifically, R ³ is —H, —Cl, —F, —CF ₃ , —OCH ₃ , —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) ₂ , —Br, —O (C ₁ -C ₄ alkyl), —CN, —C ₁ -C ₄ haloalkyl, —OH or —C ₁ -C ₄ aliphatic. Specifically, R ³ is —H, —Cl, —F, —CF ₃ , —OCH ₃ , —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) ₂ , -Br, -O (C ₁ -C ₄ alkyl), -CHCH (CH ₃ ), -CHCH ₂ , -CN, -CH ₂ CF ₃ , -CH ₂ F, -CHF ₂ , -OH or -C ₁ -C ₄ alkyl. Specifically, R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ − C ₄ alkyl) or —N (C ₁ -C ₄ alkyl) ₂ . Specifically, R ³ is -H, -F, -Cl, -CF ₃ , -NH ₂ , -NH (CH ₃ ) or -N (CH ₃ ) ₂ . Specifically, R ³ is -H, -Cl or -F. Specifically, R ³ is -Cl. Specifically, R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —CH ₃ , —C ₂ H ₅ , —O (C ₁ -C ₄ alkyl), —OH, -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ . Specifically, R ³ is -H, -F, -Cl, -CF ₃ , -CH ₃ , -C ₂ H ₅ , -NH ₂ , -NH (CH ₃ ) or -N (CH ₃ ) ₂ . Specifically, R ³ is -F or -Cl.

R ⁴ is i) a C ₃ -C ₁₀ non-aromatic carbocycle optionally substituted with one or more J ^A ; ii) J ^C ; C ₃ -C ₈ non-aromatic carbocycles or 6 to 10 membered carbocyclic aryl groups, each optionally and independently substituted with one or more J ^A ; And C ₁ optionally substituted with one or more substituents independently selected from the group consisting of a 5-10 membered heteroaryl group or a 4-10 membered non-aromatic heterocycle, each optionally and independently substituted with one or more J ^B. -C ₆ aliphatic groups such as C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups; Or iii) a 4-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B. Specifically, R ⁴ is i) an optionally substituted C ₃ -C ₁₀ carbocyclic ring; ii) C ₁ -C ₆ substituted with one or more substituents independently selected from J ^C , an optionally substituted C ₃ -C ₈ non-aromatic carbocycle and an optionally substituted 4-10 membered non-aromatic heterocycle Aliphatic groups such as C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups; Or iii) optionally substituted 4-10 membered non-aromatic heterocycle. Specifically, the C ₁ -C ₆ aliphatic group represented by R ⁴ is —OR ⁵ , —SR ⁵ , —NR′R ⁵ , —C (O) R ⁵ , —CO ₂ R ⁵ , —OC (O) R ⁵ , -C (O) NR'R ⁵ , -C (O) NRC (O) OR ⁵ , -NRC (O) NRC (O) OR ⁵ , -NRC (O) R ⁵ , -NRC (O) NR'R ⁵ , -NRCO ₂ R ⁵ , -OC (O) NR'R ⁵ , -SOR ⁵ , -SO ₂ R ⁵ , -SO ₂ NR'R ^5- , N (R) SO ₂ R ⁵ ,- NRSO ₂ NR'R ⁵ , optionally substituted C ₃ -C ₈ non-aromatic carbocycle and optionally substituted 4-10 membered non-aromatic heterocycle.

More specifically, R ⁴ is

(여기서, 환 T(후술되는 환 A, B 및 C 포함)는 하나 이상의 J^A로 임의로 치환된 C₃-C₁₀ 비-방향족 카보사이클, 또는 하나 이상의 J^B로 임의로 치환된 3원 내지 10원의 비-방향족 헤테로사이클이거나, 임의로, 환 T와 R⁹는 하나 이상의 J^A로 임의로 치환된 비-방향족 C₅-C₁₀ 카보사이클 또는 하나 이상의 J^B로 임의로 치환된 5원 내지 10원의 비-방향족 헤테로사이클을 형성한다);i)

Wherein ring T (including rings A, B and C described below) is a C ₃ -C ₁₀ non-aromatic carbocycle optionally substituted with one or more J ^A , or a 3-10 membered optionally substituted with one or more J ^B Is a non-aromatic heterocycle of, or optionally, with ring T R ⁹ forms a non-aromatic C ₅ -C ₁₀ carbocycle optionally substituted with one or more J ^A or a 5-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B );

(여기서, 환 J는 하나 이상의 J^B로 임의로 치환된 3원 내지 10원의 비-방향족 헤테로사이클이다); 또는ii)

Wherein ring J is a 3-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B ; or

(여기서, 환 D는 하나 이상의 J^D1로 임의로 치환된 4원 내지 10원의 비-방향족 헤테로사이클)이다. 더욱 구체적으로는, R⁴는,iii)

Wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more J ^D1 . More specifically, R ⁴ is

또는

이다.

or

to be.

R ⁵ is i) -H; ii) a C ₁ -C ₆ aliphatic group optionally substituted with one or more J ^C1 ; iii) a C ₃ -C ₁₀ non-aromatic carbocycle or a 6 to 10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^C1 ; Or iv) a 4-10 membered non-aromatic heterocycle or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more J ^D1 . Specifically, R ⁵ is i) -H; ii) C ₁ -C ₆ aliphatic groups optionally substituted with one or more J ^C1 (eg, C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups); iii) a C ₃ -C ₈ non-aromatic carbocycle or a 6 to 10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^C1 ; Or iv) a 4-8 membered non-aromatic heterocycle or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more J ^D1 . Optionally, R ⁵ , together with Q ¹ , Q ² and Q ^3, each optionally and independently forms a 4- to 8-membered non-aromatic ring optionally substituted with one or more J ^E1 . It is understood that the non-aromatic ring formed by R ⁵ and Q ¹ may use part of Q ¹ . In some embodiments, R ⁵ , together with Q ² and R ⁸ , optionally and independently forms a 5- to 7-membered non-aromatic ring optionally substituted with one or more J ^El .

Specifically, R ⁵ is independently i) -H; ii) a C ₁ -C ₆ -alkyl or C ₂ -C ₆ -alkenyl group optionally substituted with one or more J ^C1 ; iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; Or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 . Specifically, R ⁵ is independently i) -H; ii) a C ₁ -C ₆ -alkyl or C ₂ -C ₆ -alkenyl group, optionally and independently substituted with one or more J ^C1 ; Or iii) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more J ^D1 . Specifically, R ⁵ is independently i) -H; Or ii) a C ₁ -C ₆ -alkyl or C ₂ -C ₆ -alkenyl group, optionally and independently substituted with one or more J ^C1 .

R ⁶ and R ⁷ are each independently —H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from the group consisting of aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy, or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls. Alternatively, R ⁶ and R ⁷ are each independently —H, or a substituent halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , -C (O) OH,-(CO) O (C ₁ -C ₆ alkyl), -OC (O) (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkoxy, C _1- Optionally substituted with one or more substituents selected from the group consisting of C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Or C ₁ -C ₄ alkyl, or optionally, R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl. Specifically, R ⁶ and R ⁷ are each independently —H or —CH ₃ or together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cya Noalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy; R ⁸ together with Q ² and R ⁵ optionally and independently forms a 5- to 7-membered non-aromatic ring optionally substituted with one or more J ^El .

Each R ⁹ is independently —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ amino Alkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy; R ⁸ together with Q ² and R ⁵ optionally and independently forms a 5- to 7-membered non-aromatic ring optionally substituted with one or more J ^El . Specifically, each R ⁹ is independently —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy; R ⁸ together with Q ² and R ⁵ optionally and independently forms a 5- to 7-membered non-aromatic ring optionally substituted with one or more J ^El .

Optionally, R ⁹ and ring T form a non-aromatic C ₅ -C ₁₀ carbocycle optionally substituted with one or more J ^A or a 5-10 membered non-aromatic heterocycle optionally substituted with one or more J ^B.

Specifically, each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ ; Each R ⁹ is independently —H or C ₁ -C ₄ alkyl, more specifically —H, —CH ₃ or —CH ₂ CH ₃ .

R ¹⁰ is independently -H; Or substituents halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C _1- C ₆ hydroxyalkoxy, C ₂ -C ₆ alkoxyalkoxy, C ₃ -C ₈ non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle and 5 or 6 membered heteroaryl group A C ₁ -C ₆ alkyl group optionally substituted with one or more substituents independently selected from the group consisting of: Wherein the carbocycle, phenyl, heterocycle and heteroaryl groups for substituents of a C ₁ -C ₆ alkyl group represented by R ¹⁰ are each optionally and independently halogen, cyano, hydroxy, oxo, amino, carboxy , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, Consisting of C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Optionally substituted with one or more substituents independently selected from the group. Specifically, R ¹⁰ is independently —H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ -alkoxyalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl or C ₁ -C ₆ cyanoalkyl. Specifically, R ¹⁰ is -H, or a halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , which is a substituent -OCO (C ₁ -C _{4 alkyl), -CO 2 H, -CO 2} (C 1 -C 4 alkyl) and C ₁ -C ₄ alkoxy optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ -alkyl. Specifically, R ¹⁰ is —H or C ₁ -C ₆ -alkyl.

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl; Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls. Specifically, R ¹¹ and R ¹² are each independently —H or C ₁ -C ₄ alkyl; R ¹³ and R ¹⁴ are each independently —H or C ₁ -C ₄ alkyl, or they together with the carbon atoms to which they are attached form a cyclopropane ring. Specifically, R ¹¹ and R ¹² are each independently —H or —CH ₃ ; R ¹³ and R ¹⁴ are each independently —H, —CH ₃ or —CH ₂ CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Optionally, R ¹¹ and ring A form a bridged ring, optionally further substituted with one or more J ^A.

Ring A is a C ₃ -C ₁₀ non-aromatic carbocycle optionally further substituted with one or more J ^A , or a 3-10 membered non-aromatic heterocycle optionally further substituted with one or more J ^B. Specifically, Ring A is an optionally substituted C ₃ -C ₈ non-aromatic carbocyclic or heterocyclic ring. Specifically, Ring A is a C ₃ -C ₈ non-aromatic carbocycle optionally further substituted with one or more J ^A. Specifically, Ring A is a 4-7 membered or 5-7 membered non-aromatic carbocyclic ring optionally further substituted with one or more J ^A. An embodiment of ring A is an optionally substituted cyclohexyl or cyclopentyl ring.

Rings A and R ⁸ optionally form a 5- to 10-membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ⁹ are 5- to 10-membered non-aromatic bridged carbocycle or heterocycle Or optionally form a cycle, or rings A and R ¹¹ optionally form a 5-10 membered non-aromatic bridged carbocycle or heterocycle, wherein the carbocycle is each optionally further substituted with one or more J ^A and , Heterocycles are each optionally further substituted with one or more J ^B. In some embodiments, the bridged rings are each independently 6 to 10 members. As a representative bridged ring,

또는

이 포함되고, 여기서, 환 G1 내지 G4는 각각 독립적으로, 하나 이상의 J^A로 임의로 추가로 치환된 5원 내지 10원의 비-방향족 브릿징된 카보사이클이고, 환 G5는 하나 이상의 J^B로 임의로 추가로 치환된 5원 내지 10원의 비-방향족 브릿징된 헤테로사이클이고; R²¹, R²², R²³, R²⁴ 및 R²⁵는 각각 독립적으로, -H, 할로겐, -OH, C₁-C₆ 알콕시, 또는 치환체인 할로겐, 시아노, 옥소, 하이드록시, 아미노, 카복시, C₁-C₆ 알콕시, C₁-C₆ 할로알콕시, C₁-C₆ 아미노알콕시, C₁-C₆ 시아노알콕시, C₁-C₆ 하이드록시알콕시 및 C₂-C₆ 알콕시알콕시로 이루어진 그룹으로부터 독립적으로 선택된 하나 이상의 치환체로 임의로 치환된 C₁-C₆ 알킬이고; X는 -O-, -S- 또는 -NR^g-이고; R^g는 -H, 또는 치환체인 할로겐, 시아노, 옥소, 하이드록시, 아미노, 카복시, C₁-C₆ 알콕시, C₁-C₆ 할로알콕시, C₁-C₆ 아미노알콕시, C₁-C₆ 시아노알콕시, C₁-C₆ 하이드록시알콕시 및 C₂-C₆ 알콕시알콕시로 이루어진 그룹으로부터 독립적으로 선택된 하나 이상의 치환체로 임의로 치환된 C₁-C₆ 알킬이고; q는 0, 1 또는 2이고; x는 0, 1 또는 2이고; r은 1 또는 2이다. 상기 브릿징된 환의 추가의 예로는 아다만틸 환이 포함된다.

or

Wherein each ring G1 to G4 is each independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more J ^A , and ring G5 is optionally substituted with one or more J ^B Further substituted 5-10 membered non-aromatic bridged heterocycle; R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy With C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of; X is -O-, -S- or -NR ^g- ; R ^g is —H, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy; q is 0, 1 or 2; x is 0, 1 or 2; r is 1 or 2. Further examples of such bridged rings include adamantyl rings.

Ring B is a 4-10 membered non-aromatic heterocyclic ring optionally further substituted with one or more J ^B. Specifically, ring B is a 4-8 membered member. Specifically, Ring B is 4 to 7 or 5 to 7 members. In a specific example of ring B,

In which the rings B1 to B9 are each optionally substituted.

Ring C is a 4-10 membered non-aromatic heterocyclic ring optionally further substituted with one or more J ^B. Specifically, ring C is a 4-8 membered member. Specifically, ring C is 4-7 membered or 5-7 membered. In a specific example of ring C,

Wherein ring C1 to C5 are each optionally and independently substituted.

Ring D is a 4-10 membered non-aromatic heterocyclic ring optionally substituted with one or more J ^D1 . Specifically, ring D is 4-8 membered. Specifically, Ring D is 4 to 7 or 5 to 7 members. As a specific example of ring D,

In which the rings D1 to D7 are each optionally substituted.

Specifically, rings A to D are each a 4-8 membered or 4-7 membered ring optionally and independently substituted.

Q ¹ are each independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR) NR-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O) -, -NRC ( O) NR'-, -NRCO 2 -, -OC (O) NR'-, -S (O) -, -SO 2 -, -SO 2 NR'-, - _{NRSO 2 -, -NRSO 2 NR'-,} -P (O) (oR) O-, -OP (O) (oR a) O-, -P (O) 2 O-, -CO 2 SO 2 - , or -(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ¹ is each independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O )-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR ' _{-, -NRCO 2 -, -OC (} O) NR'-, -S (O) -, -SO 2 -, -NRSO 2 -, -SO 2 NR'-, NRSO 2 NR'- or - (CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ¹ is each independently a bond, -O-, -S-, -NR'-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NHC (O) O-, -C (O) N (CH ₃ ) C (O) O, -NHC (O) NHC (O) O-, -N (CH ₃ ) C (O) NHC (O) O-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR'-, -N (CH ₃ ) C (O) NR '-, -NHCO _2- , -N (CH ₃ ) CO _2- , -OC (O) NR'-, -S (O)-, -SO _2- , -NHSO _2- , -N (CH ₃ ) SO _2- , -SO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Q ² are each independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR ) NR-, -CO _2- , -OC (O)-, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO _2- Or-(CR ⁶ R ⁷ ) _p -Y ¹ . Specifically, Q ² is each independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O )-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR ' _{-, -NRCO 2 -, -OC (} O) NR'-, -S (O) -, -SO 2 -, -NRSO 2 -, -SO 2 NR'-, NRSO 2 NR'- or - (CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is each independently —O—, —NR′—, —C (O) —, —CO ₂ —, —C (O) NR′—, —NRC (O) —, —NRC ( _{O) NR'-, -NRCO 2 -,} -OC (O) NR'-, -NRSO 2 -, -SO 2 NR'- , or _{^{- (CR 6 R 7) p}} -Y 1 - is a. Specifically, Q ² is each independently -CO _2- , -C (O) NR'-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -NRSO ₂ -or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is each independently -NR'-, -C (O) NR'-, -NRC (O)-, -SO ₂ NR'-, -NRC (O) NR'-, -NRCO ₂ -, -OCONR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is each independently -C (O) NR'-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OCONR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is each independently —O—, —NR′—, —C (O) —, —CO ₂ —, —C (O) NR′—, —NHC (O) —, —N ( CH ₃ ) C (O)-, -NHC (O) NR'-, -N (CH ₃ ) C (O) NR'-, -NHCO _2- , -N (CH ₃ ) CO _2- , -OC ( O) NR'-, -NHSO _2- , -N (CH ₃ ) SO _2- , -SO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is each independently -CO _2- , -C (O) NR'-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR ' _{-, -N (CH 3) C} (O) NR'-, -NHCO 2 -, -N (CH 3) CO 2 -, -OC (O) NR'-, -NHSO 2 -, -N (CH 3 ) SO _2- , -SO ₂ NH-, -SO ₂ N (CH ₃ )-or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is independently -NR'-, -C (O) NR'-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR ' _{-, -N (CH 3) C} (O) NR'-, -NHCO 2 -, -N (CH 3) CO 2 -, -OCONR'- , or _{^{- (CR 6 R 7) p}} -Y 1 - is a. Specifically, Q ² is each independently -C (O) NR'-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR'-, -N ( _{CH 3) C (O) NR'-} , -NHCO 2 -, -N (CH 3) CO 2 -, -OCONR'- , or _{^{- (CR 6 R 7) p}} -Y 1 - is a.

Q ³ are each independently a bond, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR) NR-, -CO _2- , -C (O) NR-, -SO _{2- ,} -SO ₂ N (R)-, -C (O) NRC (O) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ³ is each independently a bond, -C (O)-, -C (= NR)-, -CO _2- , -C (O) NR'-, -SO _{2- ,} -SO ₂ NR'-, -C (O) NRC (O) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ³ is each independently -C (O)-, -CO _2- , -C (O) NR'-, -SO _2- , -SO ₂ NR'-, -C (O) NRC ( O) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ³ is each independently -C (O)-, -CO _2- , -C (O) NH-, -C (O) N (CH ₃ )-, -SO _{2- ,} -SO ₂ NH-, -SO ₂ N (CH ₃ )-, -C (O) NHC (O) O-, -C (O) N (CH ₃ ) C (O) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ³ is each independently -C (O)-, -CO _2- , -C (O) NR'-, -C (O) NHC (O) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ³ is each independently -C (O)-, -CO _2- , -C (O) NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Q ² and Q ³ , together with R ⁵ , may optionally and independently form a 5- to 7-membered non-aromatic ring optionally substituted with one or more J ^E1 . It is understood that the non-aromatic ring formed by R ⁵ and Q ² may use part of Q ² . It is also understood that the non-aromatic rings formed by R ⁵ and Q ³ can utilize a portion of Q ³ .

Y ¹ are each independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -C (= NR) NR-, -NRC (= NR ) NR-, -CO _2- , -OC (O)-, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O- or -CO ₂ SO _2- to be. Specifically, each Y ¹ is independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O) -, -C (O) NR'-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO _2- , -NRSO ₂ NR'-, -NRC (O) NRC (O) O- or -C (O) NRC (O) O-. Specifically, each Y ¹ is independently a bond, -O-, -NR'-, -C (O) NR'-, -NRC (O)-, -NRC (O) NR'-, -NRCO ₂ -, -OC (O) NR'-, -NRC (O) NHC (O) O- or -C (O) NHC (O) O-. Specifically, Y ¹ is each independently a bond, -O-, -S-, -NR'-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR'-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR'-, -N (CH ₃ ) C (O) NR'-, -NHCO _2- , -N (CH ₃ ) CO _2- , -OC (O) NR'-, -S (O)-, -SO _2- , -NHSO _2- , -N (CH ₃ ) SO _2- , -SO ₂ NH-, SO ₂ N (CH ₃ )-, -NHSO ₂ NH-, -N (CH ₃ ) SO ₂ NH-, -N (CH ₃ ) SO ₂ N (CH ₃ )-, -C (O) NHC (O) O-, -C (O) N (CH ₃ ) C (O) O-, -NHC (O) NHC (O) O- or -N (CH ₃ ) C (O) NHC (O) O -to be. Specifically, each Y ¹ is independently a bond, -O-, -NR'-, -C (O) NR'-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR'-, -N (CH ₃ ) C (O) NR'-, -NHCO _2- , -N (CH ₃ ) CO _2- , -OC (O) NR'-, -C ( O) NHC (O) O— or —NHC (O) NHC (O) O—.

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo, -NCO and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B each, together with the atom (s) to which they are attached, form a 4-8 membered ring optionally substituted with one or more J ^E1 (eg, a spiro ring or a fused ring) Form independently. Specifically J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo, -NCO and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B , together with the atom (s) to which they are attached, independently form a five to seven membered ring optionally substituted with one or more J ^E1 . The 5- to 7-membered ring formed of J ^A or J ^B may be aromatic or non-aromatic. The 5- to 7-membered ring formed of J ^A or J ^B may be optionally fused to the ring to which they are attached. In some embodiments, the 5- to 7-membered ring may optionally be a spiro ring formed by two cosine J ^A and two cosine J ^B , respectively.

J ^C is halogen, cyano, oxo, -OR ⁵ , -SR ⁵ , -NR'R ⁵ , -C (O) R ⁵ , -CO ₂ R ⁵ , -OC (O) R ⁵ , -C (O ^{) NR'R 5, -C (O)} NRC (O) OR 5, -NRC (O) NRC (O) OR 5, -NRC (O) R 5, -NRC (O) NR'R 5, -NRCO ₂ R ⁵ , -OC (O) NR'R ⁵ , -S (O) R ⁵ , -SO ₂ R ⁵ , -SO ₂ NR'R ⁵ , -NRSO ₂ R ⁵ , -NRSO ₂ NR'R ⁵ and -P (O) (OR ^a ) ₂ -is independently selected. Specifically, J ^C is -OR ⁵ , -SR ⁵ , -NR'R ⁵ , -C (O) R ⁵ , -CO ₂ R ⁵ , -OC (O) R ⁵ , -C (O) NR ' ^{R 5, -C (O) NRC} (O) OR 5, -NRC (O) NRC (O) OR 5, -NRC (O) R 5, -NRC (O) NR'R 5, -NRCO 2 R 5 , -OC (O) NR'R ⁵ , -S (O) R ⁵ , -SO ₂ R ⁵ , -SO ₂ NR'R ⁵ , -NRSO ₂ R ⁵ and -NRSO ₂ NR'R ⁵ Are selected independently. Specifically, J ^C is halogen, cyano, oxo, -OR ⁵ , -NR'R ⁵ , -C (O) R ⁵ , -CO ₂ R ⁵ , -OC (O) R ⁵ , -C (O ^{) NR'R 5, -C (O)} NRC (O) OR 5, -NRC (O) R 5, -NRC (O) NR'R 5, -NRCO 2 R 5 , and -OC (O) NR'R ⁵ is selected from the group consisting of. Specifically, J ^C is halogen, cyano, oxo, -OR ⁵ , -NR'R ⁵ , -C (O) R ⁵ , -CO ₂ R ⁵ , -OC (O) R ⁵ , -C (O ) NR'R ⁵ and -NRC (O) R ⁵ . Specifically, J ^C is selected from the group consisting of halogen, cyano, oxo, —OR ⁵ , —NR′R ⁵ , —C (O) NR′R ⁵ and —NRC (O) R ⁵ . Specifically, J ^C is selected from the group consisting of —OR ⁵ , —NR′R ⁵ , —C (O) NR′R ^5, and —NRC (O) R ⁵ .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (= NR) R ^c , -C (= NR) NR ^b R ^c , -NRC (= NR) NR ^b R ^c , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b , -NRSO ₂ NR ^c R ^b , -P (O) (OR ^a ) ₂ , -OP (O) (OR ^a ) _2- , -P (O) ₂ (OR ^a ) and -CO ₂ SO ₂ R ^b , or Two J ^C1 and two J ^D1 , together with the atom (s) to which they are attached, each independently form a 4-8 membered ring optionally substituted with one or more J ^E1 . Specifically, J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ) , -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b and -NRSO ₂ NR ^c R ^b .

Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 . It is to be understood that the meaning of each of J ^C1 and J ^D1 is chosen to form stable or chemically feasible compounds. For example, the suitable meanings of J ^C1 and J ^D1 on carbon atoms are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NR ^b C (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C ( O) NR (OR ^b ), —SO ₂ NR ^c R ^b , —NRSO ₂ R ^b and —NRSO ₂ NR ^c R ^b ; Suitable meanings of J ^D1 on a nitrogen atom are R ^a , -SO ₂ R ^a , -SO ₂ N (R) R ^b , -C (O) R ^b , -C (O) OR ^b , -C (O) NR ^b R ^c , —C (O) NRCO ₂ R ^b and —C (O) NR (OR ^b ). Specific examples of J ^C1 and J ^D1 on a carbon atom are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NHR ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b and -OCONHR ^c , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b , -C (O) N (CH ₃ ) CO ₂ R ^b ,- NHC (O) NHC (O) OR ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -C (O) NH (OR ^b )-, C (O) N (CH ₃ ) ( OR ^b ), -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and -N (CH ₃ ) SO ₂ R ^b . Specific examples of J ^D1 on a nitrogen atom are each independently R ^a , -SO ₂ R ^a , -C (O) R ^b , -C (O) OR ^b , -C (O) NHR ^c , -C (O ) N (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b , -C (O) N (CH ₃ ) CO ₂ R ^b , -C (O) NH (OR ^b )-and -C (O ) N (CH ₃ ) (OR ^b ) is included. More specific examples of J ^C1 and J ^D1 on a carbon atom are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl),- C (O) O (C ₁ -C ₄ alkyl), C ₃ -C ₆ cycloalkyl and -CO ₂ H, wherein the alkyl groups (eg, C ₁ -C ₄ alkyl, —O ( C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl),- OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl) and C ₃ -C ₆ cycloalkyl) are each optionally and independently halogen, cyan Furnace, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OCO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are substituted with one or more substituents independently selected from the group consisting of. More specific examples of J ^D1 on the nitrogen atom are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -C (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl) and C ₃ -C ₆ cyclo (alkyl), wherein said alkyl groups are each halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C) ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OCO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ ( Optionally and independently substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

J ^E1 are each independently halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl) and —C (O) (C ₁ -C ₆ -alkyl) independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N ( C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ Optionally and independently substituted with one or more substituents independently selected from the group consisting of -C ₄ alkoxy. Specifically, each J ^E1 is independently halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —C (O) (C ₁ -C ₆ -Alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -C (O) O (C ₁ -C ₆ alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) And -CO ₂ H, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C _1- C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ Optionally and independently substituted with one or more substituents independently selected from the group consisting of alkoxy. It should be understood that suitable J ^E1 is chosen to form stable or chemically feasible compounds. For example, suitable substituents on a carbon atom are independently halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —C (O) (C ₁ -C ₆ -alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -C (O) O (C ₁ -C ₆ alkyl) , -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl ) And -CO ₂ H, wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of: For example, suitable substituents on a nitrogen atom are independently C ₁ -C ₆ alkyl, —C (O) NH (C ₁ -C ₆ alkyl), —C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl) and -C (O) O (C ₁ -C ₆ alkyl), wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl),- Optionally and independently substituted with one or more substituents independently selected from the group consisting of CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

R and R 'are each independently -H or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ amino C ₁ -C ₆ alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of alkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy to be. Specifically, R and R 'are each independently -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C _1- C ₆ alkyl) ₂ , -C (O) O (C ₁ -C ₆ alkyl), -OC (O) (C ₁ -C ₆ alkyl), -CO ₂ H, C ₁ -C ₆ haloalkoxy, C ₁ amino -C ₆ alkoxy, cyano-C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy, and hydroxy C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkoxy optionally substituted with one or more substituents independently selected from the group consisting of Alkyl. Specifically, R and R 'are each independently -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C _1- C ₆ alkyl) ₂ and -O (C ₁ -C ₆ optionally substituted by C ₁ -C ₆ alkyl with one or more substituents independently selected from the group consisting of alkyl). Specifically, R and R 'are each independently -H or C ₁ -C ₆ alkyl (eg -CH ₃ or -CH ₂ CH ₃ ).

Optionally, R ', together with R ⁵ and the nitrogen atom to which they are attached, form a 5-7 membered non-aromatic heterocyclic ring optionally substituted with one or more J ^D1 . Specifically, the non-aromatic heterocycle is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl) , -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C ( O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ Optionally substituted with one or more substituents independently selected from the group consisting of -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), and -CO ₂ R ^b ; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO ( Independent from the group consisting of C ₁ -C ₄ alkyl), -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents selected. Specifically, the non-aromatic heterocycle is halogen, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) , -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C _1- C ₄ alkyl) optionally substituted with one or more substituents independently selected from the group consisting of: wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl) , -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from.

Each R ^* is independently: i) -H; ii) halogen, cyano, hydroxy, oxo, amino, carboxy, C ₃ -C ₈ non-aromatic carbocycle, 5- or 6-membered non-aromatic heterocycle, phenyl, 5- or 6-membered heteroaryl, -O (C ₁ -C ₆ alkyl) and _{-C (O) (C 1 -C} 6 - alkyl) C ₁ -C ₆ optionally substituted by one or more substituents independently selected from the group consisting of alkyl group [wherein said alkyl Groups (eg, alkyl groups represented by -O (C ₁ -C ₆ alkyl) and -C (O) (C ₁ -C ₆ -alkyl)) are each optionally and independently halogen, cyano, hydride Roxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ Alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy substituted with one or more substituents independently selected from the group consisting of the C ₃ -C ₈ non-aromatic carbo Cycle, 5- or 6-membered non-aromatic heterocycle, phenyl and 5- or 6-membered The heteroaryl of the circle is each independently optionally substituted with one or more J ^El ; Or iii) each independently C ₃ -C ₈ non-aromatic carbocycle or 4-8 membered non-aromatic heterocycle, optionally substituted with one or more J ^El . Specifically, R ^* is each independently i) -H; ii) halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ aminoalkoxy, C ₁ -C ₄ cyanoalkoxy, C ₁ -C ₄ alkoxy and hydroxy-C ₂ -C ₄ alkoxy-alkoxy optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ alkyl; Or iii) halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cyanoalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₄ aminoalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ aminoalkoxy, C ₁ -C ₄ cyanoalkoxy, C ₁ -C ₄ hydroxy-alkoxy and C ₂ -C ₄ alkoxyalkoxy of cyclic 3-to 7-membered independently optionally substituted with one or more substituents selected from the group consisting of carbonyl ring. Specifically, R ^* is i) -H, ii) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _Group consisting of ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from; Or iii) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl) , Independently selected from the group consisting of -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy and C ₁ -C ₆ alkyl A 3-7 membered carbocyclic ring optionally substituted with any of the above substituents, wherein said alkyl is each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl) ), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ Alkyl) and C ₁ -C ₄ alkoxy.

Each R ^a is independently i) halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O (C ₁ -C ₆ alkyl), -C (O) (C ₁ -C ₆ -alkyl ), A C ₃ -C ₈ non-aromatic carbocycle, a 4-8 membered non-aromatic heterocycle, a 5-10 membered heteroaryl group and a 6-10 membered carbocyclic aryl group C ₁ -C ₆ aliphatic groups optionally substituted with one or more independently selected substituents, wherein the alkyl groups for the substituents of the C ₁ -C ₆ aliphatic groups represented by R ^a are each halogen, cyano, Roxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ Alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy optionally and independently substituted with one or more substituents independently selected from the group consisting of; The carbocycle, heterocycle, heteroaryl and carbocyclic aryl groups for the substituents of the C ₁ -C ₆ aliphatic group represented by R ^a are each, optionally and independently substituted with one or more J ^E1 ; ii) C ₃ -C ₈ non-aromatic carbocycles or 4- to 8-membered non-aromatic heterocycles, each optionally and independently substituted with one or more J ^El ; iii) a 5-10 membered heteroaryl or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^El .

Alternatively, R ^a is each independently i) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O ) (C ₁ -C ₆ alkyl), -O (C ₁ -C ₆ alkyl), -C (O) (C ₁ -C ₆ -alkyl), C ₃ -C ₈ non-aromatic carbocycles, 6 to 10 membered carbocyclic aryl, 4 member to 8-membered non-aromatic heterocyclic group and optionally a 5-to 10-one independently selected from the group consisting of heteroaryl or more of the substituents C ₁ -C ₆ aliphatic group; wherein said R marked with ^a C ₁ - The alkyl groups for the substituents of C ₆ aliphatic groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group; The carbocycle, phenyl, non-aromatic heterocycle and heteroaryl groups for the substituents of the C ₁ -C ₆ aliphatic group represented by R ^a are each optionally and independently halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) O (C ₁ -C ₆ -alkyl),- OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -O (C ₁ -C ₆ alkyl) and -C (O) (C ₁ -C ₆ -alkyl) are substituted with one or more substituents independently selected from the group consisting of halogen, cyano, Hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy, optionally and independently substituted with one or more substituents independently selected from the group consisting of; ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O ) (C ₁ -C ₆ alkyl), C ₃ -C ₈ non- optionally and independently substituted with one or more substituents independently selected from the group consisting of —O (C ₁ -C ₆ alkyl) and —C (O) (C ₁ -C ₆ -alkyl) Aromatic carbocyclic groups or 4- to 8-membered non-aromatic heterocyclic groups wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl ), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ Optionally and independently substituted with one or more substituents independently selected from the group consisting of alkyl) and C ₁ -C ₄ alkoxy]; Or iii) halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ ,- C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -C (O) NH ₂ , -C (O) NH ( C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C ( O) (C ₁ -C ₆ alkyl), 5- to 10-membered heteroaryl groups or 6 to 10, optionally and independently substituted with one or more of -O (C ₁ -C ₆ alkyl) and -C (O) (C ₁ -C ₆ -alkyl) Original carbocyclic aryl groups, wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _Group consisting of ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from.

Specifically, R ^a is independently i) halogen; Cyano; Hydroxy; Oxo; -NH ₂ ; -NH (C ₁ -C ₆ alkyl); -N (C ₁ -C ₆ alkyl) _2; -C (O) O (C ₁ -C ₆ -alkyl); -OC (O) (C ₁ -C ₆ -alkyl); -CO ₂ H; -O (C ₁ -C ₆ alkyl); -C (O) (C ₁ -C ₆ -alkyl); And C ₃ -C ₇ non-aromatic carbocyclic groups, phenyl groups, 4- to 7-membered non-aromatic heterocyclic groups or 5- or 6-membered heteroaryl groups, wherein the groups are each optionally and independently With halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -O (C ₁ -C ₆ alkyl), and -C (O) (C ₁ -C ₆ -alkyl) substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of; ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O ) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -O (C ₁ -C ₆ alkyl), and -C (O) (C C ₃ -C ₇ non-aromatic carbocyclic group optionally substituted with one or more substituents independently selected from the group consisting of ₁ -C ₆ -alkyl); iii) halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O ) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -O (C ₁ -C ₆ alkyl), and -C (O) (C 4- to 7-membered non-aromatic heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of ₁ -C ₆ -alkyl); iv) each optionally and independently halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -O (C ₁ -C ₆ alkyl), and -C 5 or 6 membered heteroaryl group or phenyl group substituted with one or more substituents independently selected from the group consisting of (O) (C ₁ -C ₆ -alkyl). The alkyl groups mentioned in the meaning of R ^a include their substituents, respectively, halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C Optionally and independently substituted with one or more substituents independently selected from the group consisting of ₄ alkoxy.

Specifically, the optionally substituted C ₁ -C ₆ aliphatic group represented by R ^a is an optionally substituted C ₁ -C ₆ alkyl group.

R ^b and R ^c are each independently R ^a or -H; Optionally, R ^b and R ^c together with the nitrogen atom (s) to which they are attached (eg, —NR ^b R ^c , —C (O) NR ^b R ^c , —NRC (O) NR ^b R ^c Or -OCONR ^b R ^c ), each independently forming a 5-7 membered non-aromatic heterocyclic ring optionally substituted with one or more J ^E1 . Specific suitable substituents for the heterocyclic ring formed by R ^b and R ^c are independently halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl , C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ -alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy , C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, C ₂ -C ₆ alkoxyalkoxy and —C (O) (C ₁ -C ₆ -alkyl) Included. Specific suitable substituents for the heterocyclic ring formed by R ^b and R ^c are independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C _1- C ₄ alkyl) _2, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C _1- C ₄ alkoxy, C ₁ -C ₄ Haloalkoxy, C ₁ -C ₄ hydroxyalkoxy, C ₂ -C ₄ alkoxyalkoxy, -CO ₂ (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl) and -CO ₂ H Included.

It is to be understood that suitable substituents on the heterocyclic rings formed by R ^b and R ^c are chosen to form stable or chemically feasible compounds. For example, suitable substituents on a carbon atom are independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ -aminoalkoxy, C ₁ -C ₆ -cyanoalkoxy, C ₁ -C ₆ -hydroxyalkoxy, C ₂ -C ₆ -alkoxyalkoxy , -C (O) (C ₁ -C ₆ -alkyl), -C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C _1- C ₆ alkyl) and —N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl). In another example, suitable substituents on a carbon atom are independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C _1- C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₂ - C ₄ hydroxyalkoxy, C ₂ -C ₄ alkoxyalkoxy, —CO (C ₁ -C ₄ alkyl), —CO ₂ (C ₁ -C ₄ alkyl), and —CO ₂ H. For example, suitable substituents on a nitrogen atom are independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ amino Alkyl, C ₁ -C ₆ cyanoalkyl, -C (O) (C ₁ -C ₆ -alkyl), -C (O) O (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ -alkyl), -CO ₂ H, -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl) and -C (O) N (C ₁ -C ₆ alkyl) ₂ Included. In another example, suitable substituents on a nitrogen atom are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ haloalkoxy, C ₂ -C ₄ hydroxyalkoxy, -CO (C ₁ -C ₄ alkyl), -CO ₂ (C ₁ -C ₄ alkyl) and -CO ₂ H.

Each R ^d is independently —H, C ₁ -C ₆ alkyl, or —C (O) (C ₁ -C ₆ alkyl), wherein the alkyl moieties are each optionally and independently halogen, cyano, hydroxy, Oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl) , —CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are substituted with one or more substituents independently selected from the group consisting of. Specifically, each R ^d is independently -H, or a substituent, halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more groups selected.

p is independently 1, 2, 3 or 4. Specifically, p is 1 or 2 independently.

k, n and m are each independently 0, 1 or 2. Alternatively, when rings A and B are 3 to 6 members, n and m are each independently 0 or 1; k is independently 0, 1 or 2; When rings A and B are 7 or 8 members, n and m are each independently 0, 1 or 2; k is independently 0, 1 or 2.

x and y are each independently 0, 1 or 2.

z is 1 or 2.

The second set of letters of formula I and IA is as follows:

R ² is -H or -CH ₃ .

R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl) Or -N (C ₁ -C ₄ alkyl) ₂ .

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The third set of letters of formula I and IA is as follows:

R ² is -H or -CH ₃ .

R ⁴ is i) an optionally substituted C ₃ -C ₁₀ carbocyclic ring; ii) C ₁ -C ₆ substituted with one or more substituents independently selected from J ^C , an optionally substituted C ₃ -C ₈ non-aromatic carbocycle and an optionally substituted 4-10 membered non-aromatic heterocycle Aliphatic groups such as C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups; Or iii) optionally substituted 4-10 membered non-aromatic heterocycle.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The fourth set of letters of formulas I and IA is as follows:

R ² is -H or -CH ₃ .

R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl) Or -N (C ₁ -C ₄ alkyl) ₂ .

R ⁴ is selected from the formulas A to D shown above.

The remaining letters of formula (I) and (IA) are each independently as described in the first set of letters of formula (I) and (IA) above, including their specific meanings.

The fifth set of letters of formula I and IA is as follows:

R ² is -H or -CH ₃ .

R ³ is —H, —F, —Cl, —CF ₃ , —NH ₂ , —NHMe or —NMe ₂ .

R ⁴ is i) an optionally substituted C ₃ -C ₁₀ carbocyclic ring; ii) C ₁ -C ₆ substituted with one or more substituents independently selected from J ^C , an optionally substituted C ₃ -C ₈ non-aromatic carbocycle and an optionally substituted 4-10 membered non-aromatic heterocycle Aliphatic groups such as C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups; Or iii) optionally substituted 4-10 membered non-aromatic heterocycle.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The sixth set of letters of formula I and IA is as follows:

R ² is -H or -CH ₃ .

R ³ is —H, —F, —Cl, —CF ₃ , —NH ₂ , —NH (CH ₃ ) or —N (CH ₃ ) ₂ .

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The seventh set of letters of formula (I) and (IA) is as follows:

R ² is -H or -CH ₃ .

R ³ is -H, -F or -Cl.

R ⁴ is i) an optionally substituted C ₃ -C ₁₀ carbocyclic ring; ii) C ₁ -C ₆ substituted with one or more substituents independently selected from J ^C , an optionally substituted C ₃ -C ₈ non-aromatic carbocycle and an optionally substituted 4-10 membered non-aromatic heterocycle Aliphatic groups such as C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups; Or iii) optionally substituted 4-10 membered non-aromatic heterocycle.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The eighth set of letters of Formulas I and IA is as follows:

R ² is -H or -CH ₃ .

R ³ is -H, -F or -Cl.

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The ninth set of letters of formula I and IA is as follows:

R ² is -H.

R ³ is -H or -Cl.

R ⁴ is i) an optionally substituted C ₃ -C ₁₀ carbocyclic ring; ii) C ₁ -C ₆ substituted with one or more substituents independently selected from J ^C , an optionally substituted C ₃ -C ₈ non-aromatic carbocycle and an optionally substituted 4-10 membered non-aromatic heterocycle Aliphatic groups such as C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl groups; Or iii) optionally substituted 4-10 membered non-aromatic heterocycle.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The tenth set of letters of formula (I) and (IA) is as follows:

R ² is -H.

R ³ is -H or -Cl.

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The eleventh set of letters of formula I and IA is as follows:

R ² , R ³ and R ⁴ are each independently in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth set of letters of formula I and IA. As described.

Z ¹ is —H, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —F, —Cl, —CN, —CO ₂ H, —CO ₂ (C ₁ -C ₆ alkyl), -CONH ₂ , -CONH (C ₁ -C ₆ alkyl) or -CON (C ₁ -C ₆ alkyl) ₂ ; Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ego; Wherein said alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —CO ₂ (C ₁ -C ₆ alkyl), —NH (C ₁ -C ₆ alkyl) And alkyl groups represented by -N (C ₁ -C ₆ alkyl) ₂ are each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl),- N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and Substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The twelfth set of letters of formula I and IA is as follows:

R ² , R ³ and R ⁴ are each independently in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth set of letters of formula I and IA. As described.

Z ¹ is —H, —F, —Cl, C ₁ -C ₄ haloalkyl (eg —CF ₃ ), C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl) or —CN.

Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ego; Wherein said alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —NH (C ₁ -C ₆ alkyl) and —N (C ₁ -C ₆ alkyl) ₂ Alkyl groups) are optionally and independently selected from halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ ,- Independently from the group consisting of OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Substituted with one or more substituents selected.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The thirteenth set of letters of formula (I) and (IA) is as follows:

R ² , R ³ and R ⁴ are each independently a first set, second set, third set, fourth set, fifth set, sixth set, seventh set, eighth set of letters of formula I and IA , As described in the ninth or tenth set.

Z ¹ is —H, —F, —Cl, C ₁ -C ₄ haloalkyl (eg —CF ₃ ), C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl) or —CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with substituents.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

The fourteenth set of letters of Formulas I and IA is as follows:

R ² , R ³ and R ⁴ are each independently in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth set of letters of formula I and IA. As described.

Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with substituents.

The meanings of the remaining letters of the formulas (I) and (IA) are the same as described in the first set of letters of the formulas (I) and (IA), above each, including specific meanings.

In a fifteenth set of letters of formula (I) and (IA), the meanings of the letters of formula (I) and (IA), except for R ^* , R, and R ', include specific meanings, each independently of the letters of formula (I) and (IA). As described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth set of the same; If applicable,

Each R ^* is independently: i) -H; ii) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C _{4 alkyl), -CO 2 H, -CO 2} (C 1 -C 4 alkyl) and C ₁ -C ₄ alkoxy optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ alkyl; Or iii) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl) , Independently selected from the group consisting of -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy and C ₁ -C ₆ alkyl A 3-7 membered carbocyclic ring optionally substituted with the above substituents, wherein said alkyl is each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl) ), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ Alkyl) and one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy;

R and R 'are each independently -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ and -O with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) optionally substituted C ₁ -C ₆ alkyl; Optionally, R ', together with R ⁵ and the nitrogen atom to which they are attached, form a 5-7 membered non-aromatic heterocyclic ring optionally substituted with one or more J ^D1 .

The sixteenth set of letters of Formulas I and IA is as follows:

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B , together with the atom (s) to which they are attached, each independently represent a 5-7 membered ring which is optionally substituted with one or more J ^E1 and fused to the ring to which they are attached To form.

Q ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR'-,- C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR '-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO _2- , -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b and -NRSO ₂ NR ^c R ^b , or, optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, are attached And independently form a 5 to 7 membered ring to be fused to each ring to which it is optionally substituted with one or more J ^E1 .

Meaning of the remaining letters of the formula (I) and (IA), including the specific meaning, each independently of the first, second, third, fourth, fifth, sixth, seventh, fifth, of the letters of the formula (I) and (IA) As described in the eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth set.

The seventeenth set of letters of Formulas I and IA is as follows:

R ¹ is -H.

R ² is —H, —CH ₃ , —CH ₂ OH or —NH ₂ . Alternatively, R ² is -H or -CH ₂ OH.

R ³ is —H, —F, —Cl, C _1-4 alkyl or C _1-4 haloalkyl. Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is C ₁ -C ₆ alkyl optionally substituted with —H, or one or more substituents independently selected from the group consisting of the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

Z ³ is -H or C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl).

The remaining letters are as described in any set of letters of Formulas IA and I, where applicable.

An eighteenth set of letters of Formulas I and IA is as follows:

R ¹ is -H.

R ² is —H or —CH ₂ OH.

R ³ is -H, -F or -Cl. Alternatively, R ³ is -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² and Z ³ are -H.

The remaining letters are each independently as described in any set of letters of Formulas IA and I above.

The nineteenth set of letters of Formulas I and IA is as follows:

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; iv) optionally substituted 4-7 membered non-aromatic heterocycle; v) an optionally substituted phenyl group; Or vi) an optionally substituted 5 or 6 membered heteroaryl ring; Optionally, together with R and the nitrogen atom to which it is attached, form an optionally substituted 5-7 membered non-aromatic heterocycle;

The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, -NRCO (C ₁ -C ₄ alkyl ), -CONR (C ₁ -C ₄ alkyl), -NRCO ₂ (C ₁ -C ₄ alkyl), a C ₃ -C ₇ non-aromatic carbocycle optionally substituted with one or more J ^E1 substituents, one or more substituents 4- to 7-membered non-aromatic heterocycle optionally substituted with J ^El ; And one or more substituents independently selected from the group consisting of phenyl optionally substituted with one or more J ^El which is a substituent;

The carbocycle, heterocycle, phenyl and heteroaryl represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl) , -C (O) O (C 1 -C 4 alkyl) and independently with one or more substituents independently selected from the group consisting of -CO ₂ H and optionally substituted, wherein the alkyl groups are each halogen, cyano, Hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents independently selected from the group consisting of.

R ¹ , R ² , R ³ , Z ¹ , Z ² and Z ³ are each independently as described in the seventeenth or eighteenth set of characters.

The remaining letters are each independently as described in any set of letters of Formulas IA and I above.

In some embodiments, the letters of Formulas IA and I are each independently as described in any set of letters above, provided that R ⁴ is

또는

이고;

or

ego;

n and m are each independently 0 or 1 when rings A and B are 3 to 6 members; n and m are each independently 0, 1 or 2 when rings A and B are 7 to 10 members;

Provided that when Y ¹ is a bond, R ⁵ is neither -H nor a C ₁ -C ₆ aliphatic group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is neither -H nor a C ₁ -C ₆ aliphatic group.

In another aspect, the present invention relates to the use of a compound represented by any one of the formulas (II) to (V) or a pharmaceutically acceptable salt thereof for any of the uses described above.

Formula II

Formula III

Formula IV

Formula V

The first set of letters of Formulas II through V is as follows:

Z ¹ is —H, —F, —Cl, C ₁ -C ₄ haloalkyl (eg —CF ₃ ), C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl) or —CN.

Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy Optionally and independently substituted by substituents.

R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl) Or -N (C ₁ -C ₄ alkyl) ₂ . Specifically, R ³ is -H, -F, -Cl, -CF ₃ , -NH ₂ , -NH (CH ₃ ) or -N (CH ₃ ) ₂ . Specifically, R ³ is -H, -Cl or -F. Specifically, R ³ is -Cl.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The definitions of rings A to D of formulas (II) to (V) are as described in the first set of letters of formula (I) and (IA), each independently including specific characters, wherein rings A to D are each optionally and independently. It is a 4 to 7 membered ring substituted with.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first set of letters of the formulas (I) and (IA), each independently including a specific meaning.

The second set of letters of formula II to V is as follows:

Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with substituents.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first set of letters of the formulas (II) to (V), each independently including a specific meaning.

The third set of letters of formulas II to V is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with substituents.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first set of letters of the formulas (II) to (V), each independently including a specific meaning.

The fourth set of letters of formulas II to V is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with substituents.

R ³ is -H, -Cl or -F.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first set of letters of the formulas (II) to (V), each independently including a specific meaning.

The fifth set of letters of formula II to V is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with substituents.

R ³ is —H, —Cl, —F, —CF ₃ , —NH ₂ , —NH (CH ₃ ) or —N (CH ₃ ) ₂ .

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first set of letters of the formulas (II) to (V), each independently including a specific meaning.

The sixth set of letters of Formulas II through V is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or optionally substituted C ₁ -C ₆ alkyl.

R ³ is -H, -Cl or -F.

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first set of letters of the formulas (II) to (V), each independently including a specific meaning.

In the seventh set of letters of Formulas II to V, the meanings of the letters of Formulas II to V are specified, except R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ . Each independently as defined above in the first, second, third or fourth set of letters of Formulas II to V;

R ⁶ and R ⁷ are each independently —H or —C ₁ -C ₄ alkyl, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —C ₁ -C ₄ alkyl.

R ¹¹ and R ¹² are each independently —H or —C ₁ -C ₄ alkyl.

R ¹³ and R ¹⁴ are each independently —H or —C ₁ -C ₄ alkyl, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

In the eighth set of letters of formulas (II) to (V), the meanings of the letters of formulas (II) to (V) are each independently as described in the first set of letters of formulas (II) to (V), including the specific meanings.

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A rather than -H.

Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group (eg, a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group); Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. In one embodiment, the C ₁ -C ₆ aliphatic group is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In the ninth set of letters of formulas II to V, the meanings of the letters of formulas II to V are each independently as described in the first set of letters of formulas I and IA, including specific meanings.

The tenth set of letters of Formulas II to V is as follows:

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B , together with the atom (s) to which they are attached, each independently represent a 5-7 membered ring which is optionally substituted with one or more J ^E1 and fused to the ring to which they are attached To form.

Q ¹ is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR-, -C ( O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-,- S (O) —, —SO ₂ —, —N (R) SO ₂ —, —SO ₂ N (R) —, —NRSO ₂ NR— or — (CR ⁶ R ⁷ ) _p -Y ^1- .

Q ² is independently a bond, -O-, -S-, -NR-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR-, -C ( O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-,- S (O) —, —SO ₂ —, —N (R) SO ₂ —, —SO ₂ N (R) —, —NRSO ₂ NR— or — (CR ⁶ R ⁷ ) _p -Y ^1- .

Q ³ is, independently, a bond, -C (O)-, -CO _2- , -C (O) NR-, -SO _{2- ,} -SO ₂ N (R)-, -C (O) NRC (O ) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

R ⁵ is i) -H; ii) a C ₁ -C ₆ aliphatic group optionally substituted with one or more J ^C1 ; iii) a C ₃ -C ₈ non-aromatic carbocycle or a 6 to 10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^C1 ; Or iv) a 4-8 membered non-aromatic heterocycle or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more J ^D1 .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b and -NRSO ₂ NR ^c R ^b , or, optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, are attached And independently form a 5 to 7 membered ring to be fused to each ring to which it is optionally substituted with one or more J ^E1 .

Ring A is a C ₃ -C ₈ non-aromatic carbocycle optionally and independently further substituted with one or more J ^A.

Meaning of the remaining characters of the formula (II) to V, including the specific meaning, each independently of the first, second, third, fourth, fifth, sixth, seventh, fifth, of the characters of the formula (II) As described in the eighth or ninth set.

In another aspect, the present invention relates to the use of a compound represented by the formula XIA or XIB or a pharmaceutically acceptable salt thereof for any of the uses described above.

Chemical Formula XIA

Formula XIB

The first set of letters of formula XIA and XIB is as follows:

Ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N 5- to 7-membered non-substituted optionally further substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Aromatic carbocyclic ring; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO Independently selected from the group consisting of (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents. Specifically, ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C _Is a 5- to 7-membered non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of ₁ -C ₄ alkyl), wherein the alkyl groups are halogen, cyano, Roxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ Alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents independently selected from the group consisting of. Specifically, ring A is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, 5- to 7-membered carbocyclic rings optionally further substituted with one or more substituents independently selected from the group consisting of C ₂ -C ₄ alkoxyalkoxy, -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) to be.

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The second set of letters of formula XIA and XIB is as follows:

Ring A, R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the first set of letters of the formulas XIA and XIB above.

The variable x is 0 or 1 and the variable n is 0 or 1.

The meanings of the remaining characters of formulas XIA and XIB are the same as described in the first set of characters of formulas I and IA, each independently including the specific meaning.

The third set of letters of formulas XIA and XIB is as follows:

Ring A, R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the second set of letters of the formulas XIA and XIB above.

Q ² is -O-, -NR'-, -CO-, -CO _2- , -C (O) NR'-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OCONR'-, -NRSO _2- , -SO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is -O-, -NH-, -N (CH ₃ )-, -C (O)-, -CO _2- , -C (O) NH-, -C (O) N ( CH ₃ )-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR'-, -N (CH ₃ ) C (O) NR'-, -NHCO ₂ -, -N (CH ₃ ) CO _2- , -OC (O) NR'-, -NHSO _2- , -N (CH ₃ ) SO _2- , -SO ₂ NH-, -SO ₂ N (CH ₃ ) -Or-(CR ⁶ R ⁷ ) _p -Y ^1- .

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The fourth set of letters of formulas XIA and XIB is as follows:

Ring A, Q ² , R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the third set of letters of the formulas XIA and XIB above.

R ⁵ is independently i) -H; ii) C ₁ -C ₆ -aliphatic groups optionally substituted with one or more J ^C1 (eg, C ₁ -C ₆ -alkyl or C ₂ -C ₆ -alkenyl groups); iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; Or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 .

^{C1 D1} J and J are each independently halogen, cyano, ^{oxo, R a, -OR b, -SR} b, -S (O) R a -, -SO 2 R a, -NHR c, -C ( O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b , -OCONHR ^c , -NHC (O) NHC (O) OR ^b , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b ,- C (O) N (CH ₃ ) CO ₂ R ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and -N (CH ₃ ) SO ₂ R ^b .

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The fifth set of letters of formula XIA and XIB is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the fourth set of letters of the formulas XIA and XIB above.

Ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C Optionally substituted with one or more substituents independently selected from the group consisting of ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Further substituted, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C _1- C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ Optionally and independently substituted with one or more substituents independently selected from the group consisting of alkoxy.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The sixth set of letters of formulas XIA and XIB is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the fifth set of letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

Wherein Rings A1 to A27 are each independently optionally further substituted with one or more substituents. Suitable substituents are as described for ring A in the first set of letters of the formulas XIA and XIB above.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The seventh set of letters of formulas XIA and XIB is as follows:

Group-[CR ¹³ R ¹⁴ ] _x -ring AQ ² -R ⁵ , Q ² , R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the sixth set of letters of the formulas XIA and XIB.

Each R ⁵ is independently i) -H; ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), Optionally with one or more substituents independently selected from the group consisting of —CO ₂ H, C ₃ -C ₈ non-aromatic carbocycles, phenyl, 4- to 8-membered non-aromatic heterocycles and 5- or 6-membered heteroaryls Substituted C ₁ -C ₆ -aliphatic groups; Or iii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ C ₃ -C ₇ non-aromatic carbocycle, 4- to 7-membered non-aromatic heterocycle, phenyl group, optionally and independently substituted with one or more substituents independently selected from the group consisting of alkyl) and -CO ₂ H Or a 5 or 6 membered heteroaryl ring; Wherein the alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R ⁵ are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C Optionally and independently substituted with one or more substituents independently selected from the group consisting of ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy; The carbocycle, phenyl, heterocycle and heteroaryl for the substituents of the C ₁ -C ₆ -aliphatic group represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ Independently and optionally substituted with one or more substituents independently selected from the group consisting of H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The eighth set of letters of formulas XIA and XIB is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the seventh set of letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

여기서, 환 A6, A8, A11, A14 및 A15는 각각 임의로 그리고 독립적으로 추가로 치환된다.

Wherein the rings A6, A8, A11, A14 and A15 are each optionally and independently substituted.

R ⁸ is independently halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, —O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The ninth set of letters of formula XIA and XIB is as follows:

Group-[CR ¹³ R ¹⁴ ] _x -ring AQ ² -R ⁵ , Q ² , R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the eighth set of letters of the formulas XIA and XIB.

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or iv) an optionally substituted 4-7 membered non-aromatic heterocycle. The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₇ Optionally substituted with one or more substituents independently selected from the group consisting of non-aromatic carbocycles and optionally substituted 4-7 membered non-aromatic heterocycles. Wherein the carbocycle and heterocycle represented by R ^5, and R ⁵ wherein the C ₁ of the carbocycle and the heterocycle mentioned for the substituent -C ₆ alkyl group represented by each, halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) One independently selected from the group consisting of (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), and -CO ₂ H Independently and optionally substituted with one or more substituents, wherein the alkyl groups (eg, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH (C ₁ -C ₄ alkyl), — N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl) and -C (O) O (C ₁ -C _4, the alkyl group represented by alkyl)) are each optionally and independently halogen, cyano, hydroxy, _{oxo, -NH 2, -NH (C 1} -C 4 alkyl), -N (C ₁ -C ₄ alkyl) _2, -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ Kiel), is replaced by a _{-CO 2 H, -CO 2 (C} 1 -C 4 alkyl) and C ₁ -C ₄ alkoxy group one or more substituents independently selected from the group consisting of.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The tenth set of letters of formulas XIA and XIB is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the seventh set of letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

여기서, 환 A1 내지 A4, A7 내지 A20, A22, A23, A25 및 A27은 각각 임의로 그리고 독립적으로 추가로 치환된다. 적합한 치환체들은 상기 화학식 XIA 및 XIB의 문자들의 제1 세트에서 환 A에 대해 기술된 바와 같다.

Wherein the rings A1 to A4, A7 to A20, A22, A23, A25 and A27 are each optionally and independently substituted. Suitable substituents are as described for ring A in the first set of letters of the formulas XIA and XIB above.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The eleventh set of characters of formulas XIA and XIB is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the seventh set of letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

Wherein rings A5 to A7, A21, A24 and A26 are each optionally further and independently substituted. Suitable substituents are as described for ring A in the first set of letters of the formulas XIA and XIB above.

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

In the twelfth set of letters of the formulas XIA and XIB, the meanings of the letters of the formulas XIA and XIB are each independently as described in the first set of letters of the formulas I and IA, including specific meanings.

In the thirteenth set of letters of formulas XIA and XIB, the meanings of the letters of formulas XIA and XIB, including the specific meanings, are each independently the sixteenth set of letters of formulas I and IA or the letters of formulas II to V As described in the tenth set.

In another aspect, the invention relates to the use of a compound represented by the formula XIIA or XIIB or a pharmaceutically acceptable salt thereof for any of the uses described above.

Formula XIIA

Formula XIIB

The first set of letters of formulas XIIA and XIIB is as follows:

Ring B is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N 4- to 7-membered non-optionally further substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Aromatic heterocyclic ring; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO Independently selected from the group consisting of (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents. Specifically, ring B is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), One independently selected from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Optionally further substituted with the above substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group. Specifically, ring B is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, Optionally further substituted with one or more substituents independently selected from the group consisting of C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H and —CO ₂ (C ₁ -C ₄ alkyl).

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R ⁹ is -H or -CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The second set of letters of formulas XIIA and XIIB is as follows:

Ring B, R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the first set of letters of the formulas XIIA and XIIB above.

The variable y is zero or one.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The third set of letters of formulas XIIA and XIIB is as follows:

Ring B, R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the second set of letters of the formulas XIIA and XIIB above.

Q ³ is independently -C (O)-, -CO _2- , -C (O) NH-, -C (O) N (CH ₃ )-, -C (O) NHC (O) O-,- C (O) N (CH ₃ ) C (O) O-, -SO _2- , -SO ₂ NH-, -SO ₂ N (CH ₃ )-or-(CR ⁶ R ⁷ ) _p -Y ^1- .

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The fourth set of letters of formulas XIIA and XIIB is as follows:

Ring B, Q ³ , R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the third set of letters of the formulas XIIA and XIIB above.

R ⁵ is independently i) -H; ii) C ₁ -C ₆ -aliphatic groups optionally substituted with one or more J ^C1 (eg, C ₁ -C ₆ -alkyl or C ₂ -C ₆ -alkenyl groups); iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -SOR ^a , -SO ₂ R ^a , -NHR ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b , -OCONHR ^c , -NHC (O) NHC (O) OR ^b , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c ,- N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b , -C (O) N (CH ₃ ) CO ₂ R ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and- N (CH ₃ ) SO ₂ R ^b .

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The fifth set of letters of formulas XIIA and XIIB is as follows:

Ring B, Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the fourth set of letters of the formulas XIIA and XIIB above.

Ring B is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl) with one or more substituents independently selected from the group consisting of Optionally further substituted, wherein said alkyl groups are each halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) _2, -OCO Independently selected from the group consisting of (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The sixth set of letters of formulas XIIA and XIIB is as follows:

Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the fifth set of letters of the formulas XIIA and XIIB.

Ring B is independently selected from one of the following structures:

Wherein ring B1 to B9 are each optionally and independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C _1- C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Substituted with one or more substituents independently selected from: wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of: Specifically, rings B1 to B9 are each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C Substituted with one or more substituents independently selected from the group consisting of _1- C ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl).

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The seventh set of letters of formulas XIIA and XIIB is as follows:

Ring B, Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the sixth set of letters of the formulas XIIA and XIIB.

Each R ⁵ is independently i) -H; ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), Optionally with one or more substituents independently selected from the group consisting of —CO ₂ H, C ₃ -C ₈ non-aromatic carbocycles, phenyl, 4- to 8-membered non-aromatic heterocycles and 5- or 6-membered heteroaryls Substituted C ₁ -C ₆ -aliphatic groups; Or iii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ C ₃ -C ₇ non-aromatic carbocycle, 4- to 7-membered non-aromatic heterocycle, phenyl group, optionally and independently substituted with one or more substituents independently selected from the group consisting of alkyl) and -CO ₂ H Or a 5 or 6 membered heteroaryl ring; Wherein the alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R ⁵ are halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ −) C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy optionally and independently substituted with one or more substituents independently selected from the group consisting of; Wherein the carbocycle, phenyl, heterocycle and heteroaryl for the substituents of the C ₁ -C ₆ -aliphatic group represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl,- NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO Independently and optionally substituted with one or more substituents independently selected from the group consisting of ₂ H, —CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

The eighth set of letters of formulas XIIA and XIIB is as follows:

Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the seventh set of letters of the formulas XIIA and XIIB.

Group (ring B) -Q ³ -R ⁵ is,

이고,

ego,

Wherein ring B2 is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, C ₂ -C ₄ alkoxycarbonyl, -CO ₂ H is replaced by -CO ₂ and optionally with one or more substituents independently selected from the group consisting of (C ₁ -C ₄ alkyl) and independently added.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning .

The ninth set of letters of formulas XIIA and XIIB are as follows:

Group (ring B) -Q ³ -R ⁵ , Q ³ , R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the eighth set of letters of the formulas XIIA and XIIB.

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or iv) an optionally substituted 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ Alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₇ non-aromatic carbocycle and optionally substituted one or more substituents independently selected from the group consisting of 4 to 7 membered non-aromatic heterocycles. Is substituted. Wherein the carbocycle and heterocycle represented by R ^5, and R ⁵ wherein the C ₁ of the carbocycle and the heterocycle mentioned for the substituent -C ₆ alkyl group represented by each, halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) One independently selected from the group consisting of (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), and -CO ₂ H Independently and optionally substituted with one or more substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Substituted with one or more substituents optionally and independently selected from the group.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first set of letters of formulas I and IA, each independently including the specific meaning.

In the tenth set of letters of the formulas XIIA and XIIB, the meanings of the letters of the formulas XIIA and XIIB are each independently as described in the first set of letters of the formulas I and IA, including specific meanings.

In the eleventh set of letters of the formulas XIIA and XIIB, the meanings of the letters of the formulas XIIA and XIIB, including the specific meanings, each independently represent the sixteenth set of the letters of the formulas I and IA or the letters of the formulas II to V. As described in the tenth set.

In another aspect, the present invention relates generally to the use of a compound represented by the formula (XIII) or a pharmaceutically acceptable salt thereof for any of the uses described above.

Formula XIII

The first set of letters of formula XIII is as follows:

Ring C is halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl ) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C 5- to 7-membered non-aromatic hetero optionally substituted with one or more substituents independently selected from the group consisting of _1- C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Cyclic rings; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of: Specifically, ring C is halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N One or more substituents independently selected from the group consisting of (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Optionally further substituted, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C _1- Optionally and independently substituted with one or more substituents independently selected from the group consisting of C ₄ alkoxy. Specifically, ring C is halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, is substituted with -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl), optionally added with one or more substituents independently selected from the group consisting of.

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R ⁹ is -H or -CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The meanings of the remaining letters of formula (XIII) are the same as described in the first set of letters of formula (I) and (IA), each independently including the specific meaning .

The second set of letters of formula XIII is as follows:

The meanings of rings C, R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ and R ¹² , including the specific meanings, are each independently as described in the first set of letters of formula XIII.

R ¹⁰ is —H or C ₁ -C ₆ -alkyl.

The meanings of the remaining letters of formula (XIII) are the same as described in the first set of letters of formula (I) and (IA), each independently including the specific meaning .

The third set of letters of formula XIII is as follows:

The meanings of R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , including the specific meanings, are each independently as described in the first set of letters of formula XIII.

Ring C is halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C _1- C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) optionally further one or more substituents independently selected from the group consisting of Substituted 5-7 membered non-aromatic, heterocyclic group wherein the alkyl groups are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , —NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ ( Optionally and independently substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The meanings of the remaining letters of formula (XIII) are the same as described in the first set of letters of formula (I) and (IA), each independently including the specific meaning .

The fourth set of letters of formula XIII is as follows:

The meanings of R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , including the specific meanings, are each independently as described in the second set of letters of formula XIII.

Ring C is

Are independently selected from, wherein the rings C1 to C5 are each optionally and independently substituted. Suitable substituents are as described for ring C in the first set of letters of formula XIV.

The meanings of the remaining letters of the formula (XIII) are the same as described in the first set of letters of the formula (I) and (IA), each independently including the specific meaning.

In the fifth set of letters of the formula (XIII), the meanings of the letters of the formula (XIII) are each independently as described in the first set of letters of the formulas (I) and (IA) above, including specific meanings.

In another aspect, the present invention generally relates to the use of a compound represented by the formula (XIV) or a pharmaceutically acceptable salt thereof for any of the uses described above.

Formula XIV

The first set of letters of formula XIV is as follows:

Ring D is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N 4- to 7-membered non-aromatic hetero optionally substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Cyclic rings; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of: Specifically, ring D is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), One independently selected from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Optionally further substituted with the above substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C Optionally and independently substituted with one or more substituents independently selected from the group consisting of _1- C ₄ alkoxy. Specifically, ring D is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, Optionally further substituted with one or more substituents independently selected from the group consisting of C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H and —CO ₂ (C ₁ -C ₄ alkyl).

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The meanings of the remaining letters of formula (XIV) are as described in the first set of letters of formula (I) and (IA), each independently including the specific meaning .

The second set of letters of formula XIV is as follows:

The meanings of the rings D, R, R ', R ⁶ , R ⁷ , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the first set of letters of the formula XIV.

z means 1.

The meanings of the remaining letters of formula (XIV) are as described in the first set of letters of formula (I) and (IA), each independently including the specific meaning .

The third set of letters of formula IV is as follows:

The meanings of z, R, R ', R ⁶ , R ⁷ , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the second set of letters of the formula XIV.

Ring D is

Independently selected from the group consisting of: wherein rings D1 to D7 are each optionally and independently substituted. Suitable substituents are as described for ring D in the first set of letters of formula XIV above.

Each R ^d is independently —H, C ₁ -C ₆ alkyl, or —C (O) (C ₁ -C ₆ alkyl), wherein the alkyl moieties are each and optionally independently halogen, cyano, hydroxy, Oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO ( C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy. Specifically, each R ^d is independently -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl),- N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and with one or more groups selected from C ₁ -C ₄ alkoxy and is optionally independently substituted with C ₁ -C ₆ alkyl.

The meanings of the remaining letters of formula (XIV) are as described in the first set of letters of formula (I) and (IA), each independently including the specific meaning.

In the fourth set of letters of formula XIV, the meanings of the letters of formula XIV are as described in the first set of letters of formulas I and IA independently of each other, including specific meanings.

In another embodiment, the compounds of Formulas I-IV and XI-XIV and pharmaceutically acceptable salts thereof are as independently described above; However, if applicable, in the case of Y ¹ are bonded, R ⁵ is neither an unsubstituted C ₁ -C ₆ aliphatic not a -H group. Specifically, when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; And an optionally substituted 5-10 membered heteroaryl group. Specifically, a C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And —NRSO ₂ NR ^c R ^b , or, optionally, two J ^C1 and two J ^D1 are each, together with the atoms to which they are attached, fused to each ring to which they are attached; A 7-membered ring is formed independently, which ring is optionally substituted with one or more J ^El .

In another embodiment, the compounds of Formulas IA-IV and XI-XIV and pharmaceutically acceptable salts thereof are independently as described above; However, if applicable, in the case of Q ² are bonded, R ⁵ is not a -H C ₁ -C ₆ nor aliphatic group; Provided that when Q ³ is a bond, R ⁵ is neither -H nor a C ₁ -C ₆ aliphatic group. Specifically, when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. Specifically, when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Or an optionally substituted 4-8 membered non-aromatic heterocycle.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula I, wherein the letters of the formula are each independently as defined above; here,

R ⁴ is

이다.

to be.

Ring E is a C ₄ -C ₈ non-aromatic carbocycle optionally further substituted with one or more J ^A.

Ring F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more J ^El .

Rings G1 and G2 are each independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more J ^A.

Q ² is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO ₂ -,- OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or iv) an optionally substituted 4-7 membered non-aromatic heterocycle; Optionally together with R and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered non-aromatic heterocycle. Alkyl groups represented by R ⁵ include halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _1- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₇ non- Optionally substituted with one or more substituents independently selected from the group consisting of aromatic carbocycles and optionally substituted 4-7 membered non-aromatic heterocycles; Here, the indicated by the carbocycle and heterocycle represented by R ^5, and R ⁵ C ₁ -C ₆ of the carbocycle and the heterocycle mentioned for the substituent of the alkyl group, respectively, halogen, cyano, hydroxy, Oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C ( Independently from the group consisting of O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl) and -CO ₂ H Independently and optionally substituted with one or more substituents selected, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C _1- C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ Optionally and independently substituted with one or more substituents independently selected from the group consisting of alkoxy.

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ Alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl; Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls.

R ²¹ , R ²² , R ²³ and R ²⁴ are each independently —H, halogen, —OH, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ One or more substituents independently selected from the group consisting of -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Optionally substituted C ₁ -C ₆ alkyl.

p and q are each independently 0, 1 or 2.

x is 0, 1 or 2.

r is 1 or 2.

The meanings of the remaining letters of formula (I), including the specific meanings, are each independently as described in any one of the first to fifteen sets of letters of formula (I).

In another embodiment, the compounds represented by formula (I) or pharmaceutically acceptable salts thereof are independently as described above in the preceding sections; Ring F is selected from any one of rings F1 to F6:

;

;

Rings F1 to F6 are each optionally and independently substituted;

Each R ^f is independently —H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, cyano C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy, and hydroxy is hydroxy C ₂ -C ₆ alkoxyalkoxy groups independently optionally substituted with one or more substituents and independently represent a substituted C ₁ -C ₆ alkyl from consisting of.

In another embodiment, the compounds represented by formula XIA or XIB or pharmaceutically acceptable salts thereof are as described above;

Group-[C (R ¹³ R ¹⁴ )] _x -ring AQ ² -R ⁵ are independently,

이고; 여기서,

ego; here,

Rings A14 and A28 are each optionally further independently and independently substituted;

The meanings of the remaining characters of the formulas XIA and XIB are the same as described in any one of the first to eleventh sets of characters of the formulas XIA and XIB, each independently including a specific meaning.

In another embodiment, the compounds represented by formula XIA or XIB, or a pharmaceutically acceptable salt thereof, are independently as described above in the preceding sections; R ⁵ is an optionally substituted C ₁ -C ₆ alkyl group; Optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or an optionally substituted 4-7 membered non-aromatic heterocycle; Optionally together with R and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered non-aromatic heterocycle. Specifically, R ⁵ is an optionally substituted 4-7 membered non-aromatic heterocycle; Optionally together with R and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered non-aromatic heterocycle.

In another embodiment, such compounds or pharmaceutically acceptable salts are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Ring E is a C ₄ -C ₁₀ non-aromatic carbocycle optionally further substituted with one or more J ^A.

Ring F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more J ^El . In a specific example of ring F,

이 포함된다.

This includes.

이 포함된다. 환 F1 내지 F7은 각각 임의로 그리고 독립적으로 치환된다. 환 F(환 F1 내지 F7 포함)를 위한 대표적인 치환체로는 할로겐, 시아노, 하이드록시, C₁-C₄ 알콕시, 및 치환체인 할로겐, 시아노, 하이드록시 및 -O(C₁-C₄ 알킬)로 이루어진 그룹으로부터 선택된 하나 이상의 치환체로 임의로 치환된 C₁-C₄ 알킬이 포함된다.An additional example is

This includes. Rings F1 to F7 are each optionally and independently substituted. Representative substituents for ring F (including rings F1 to F7) include halogen, cyano, hydroxy, C ₁ -C ₄ alkoxy, and the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl) C ₁ -C ₄ alkyl optionally substituted with one or more substituents selected from the group consisting of:

R ^f is independently —H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C C ₁ -C ₆ alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of _1- C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy.

R ⁹ is, independently, —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ Alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy , C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy or C ₂ -C ₆ alkoxyalkoxy.

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl.

Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls.

s is 0, 1 or 2.

x is 0, 1 or 2.

The remaining letters are each independently as described in any one of the sets of letters for Formulas IA and I above.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula I or IA, wherein

Ring E is a C ₄ -C ₈ non-aromatic carbocycle optionally further substituted with one or more J ^A.

R ⁹ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl,- O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl) or —N (C ₁ -C ₄ alkyl) ₂ .

The other characters are each independently as described in the previous section.

In another embodiment, such compounds or pharmaceutically acceptable salts are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Rings G1 to G4 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^A.

Ring G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^B.

X is -O-, -S- or -NR ^g- .

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _1- C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy or C ₂ -C ₆ alkoxyalkoxy.

R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _1- C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy to be.

Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls.

R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy With C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of: Specifically, R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently -H, halogen, -OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC Consisting of (O) (C ₁ -C ₆ alkyl), —NHC (O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

R ^g is —H, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy.

q is 0, 1 or 2; x is 0, 1 or 2; r is 1 or 2.

The remaining letters are each independently as described in any set of letters for Formulas IA and I above.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein

이고,R ⁴ is

ego,

Wherein rings G 1 and G 2 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^A.

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ Alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

R ²¹ , R ²² , R ²³ and R ²⁴ are each independently —H, halogen, —OH, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ One or more substituents independently selected from the group consisting of -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Optionally substituted C ₁ -C ₆ alkyl.

Q ² is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO ₂ -,- OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Alternatively, Q ² is independently -O-, -CO _2- , -OC (O)-, -C (O) NR-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -CO ₂ SO _2- , -P (O) ₂ O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . In contrast, Q ² is independently —O— or —CO ₂ —.

In some embodiments, rings E and G (including rings G1 to G5) are optionally and independently further substituted with one or more J ^A (for carbocycles) or J ^B (for heterocycles), wherein J ^A and J ^B is each independently selected from the group consisting of halogen, cyano, oxo, -NCO and Q ¹ -R ⁵ , wherein

Q ¹ is independently a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO ₂ -,- OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- ; Y ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO ₂ -, -OC (O) NR'-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO ₂ -or -NRSO ₂ NR'-.

Alternatively, Q ¹ is independently a bond, -O-, -S-, -NR-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR-,- C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR- , -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- ; Y ¹ is independently —O—, —CO ₂ —, —OC (O) —, —C (O) NR—, —NRC (O) —, —NRC (O) NR—, —NRCO ₂ — or — OC (O) NR-.

In another embodiment, Q ¹ and Y ¹ are each independently as described above in the preceding paragraphs,

R ⁵ is independently i) -H; ii) a C ₁ -C ₆ -aliphatic group optionally substituted with one or more J ^C1 ; iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 ;

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NHR ^c , -C (O ) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b , -OCONHR ^c , -NHC (O) NHC (O) OR ^b , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b , -C (O) N (CH ₃ ) CO ₂ R ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and —N (CH ₃ ) SO ₂ R ^b .

In some specific embodiments, such compounds are represented by Formula IA or I, wherein

R ¹ is -H.

R ² is —H, —CH ₃ , —CH ₂ OH or —NH ₂ . Specifically, R ² is -H or -CH ₂ OH.

R ³ is —H, —F, —Cl, C _1-4 alkyl or C _1-4 haloalkyl. Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is C ₁ -C ₆ alkyl optionally substituted with —H, or one or more substituents independently selected from the group consisting of the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

Z ³ is -H or C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl).

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; iv) optionally substituted 4-7 membered non-aromatic heterocycle; v) an optionally substituted phenyl group; vi) an optionally substituted 5- or 6-membered heteroaryl ring; Optionally, together with R and the nitrogen atom to which it is attached, form an optionally substituted 5-7 membered non-aromatic heterocycle;

The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, -NRCO (C ₁ -C ₄ alkyl ), -CONR (C ₁ -C ₄ alkyl), -NRCO ₂ (C ₁ -C ₄ alkyl), a C ₃ -C ₇ non-aromatic carbocycle optionally substituted with one or more J ^E1 substituents, one or more substituents of an optionally substituted 4-to 7-J as ^E1 non-aromatic heterocycle, and is optionally substituted with one or more substituents independently selected from the group consisting of optionally substituted phenyl as a substituent, one or more J ^E1;

Wherein the carbocycle, heterocycle, phenyl and heteroaryl represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ Alkyl), —C (O) O (C ₁ -C ₄ alkyl) and —CO ₂ H independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cya Furnace, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ Optionally and independently substituted with one or more substituents independently selected from the group consisting of -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The remaining characters, including R ⁴ , comprising a spiro ring represented by rings E and F or a bridged ring represented by rings G1 to G5, are each independently as described in any one of the preceding four embodiments. same.

In another embodiment, the compounds are represented by Formula IA or I, wherein the meanings of the letters are each independently as described in the preceding embodiments, provided that

Z ² is -H;

Z ³ is -H;

R ⁵ is independently i) -H or ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O ) O (C ₁ -C _{4 alkyl), -CO 2 H, C 3} -C 8 non-aromatic heterocyclic group of the heteroaryl, phenyl and 5-or 6-membered aromatic carbocycle, a 4-to 8-membered non- A C ₁ -C ₆ -alkyl group optionally substituted with one or more substituents independently selected from the group consisting of;

Wherein the alkyl groups mentioned in the substituents of the C ₁ -C ₆ -alkyl groups represented by R ⁵ are each halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C ₄ alkyl) , -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl ) And optionally one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy;

Wherein the carbocycle, phenyl, heterocycle and heteroaryl mentioned in the substituents of the C ₁ -C ₆ -alkyl group represented by R ⁵ are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), Independently and optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

In another embodiment, rings E, G1 through G5 are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b optionally substituted with one or more substituents selected from the group consisting of; Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _1- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy Optionally and independently. Specifically, rings E, G1 to G5 are each independently halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ ,- OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, and a halogen which is a substituent, Optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Ring A is a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ⁸ optionally form a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ⁹ optionally form a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ¹¹ optionally form a 5-10 membered non-aromatic bridged carbocycle or Forming a heterocycle, wherein the carbocycles are each independently optionally substituted with one or more J ^A , and the carbocycles are each independently and optionally substituted with one or more J ^B.

R ¹ is -H.

R ² is —H, —CH ₃ , —CH ₂ OH or —NH ₂ . Specifically, R ² is -H or -CH ₂ OH.

R ³ is —H, —F, —Cl, C _1-4 alkyl (eg —CH ₃ or —C ₂ H ₅ ) or C _1-4 haloalkyl (eg —CF ₃ ). Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is C ₁ -C ₆ alkyl optionally substituted with —H, or one or more substituents independently selected from the group consisting of the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

Z ³ is -H or C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl).

Q ² is independently -O-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O)-,- NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Y ¹ is -O-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O)-, -NRC ( O) NR'-, -NRCO _2- , -OC (O) NR'-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O -Or -CO ₂ SO _2- .

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; iv) optionally substituted 4-7 membered non-aromatic heterocycle; v) an optionally substituted phenyl group; vi) an optionally substituted 5- or 6-membered heteroaryl ring; Optionally, together with R and the nitrogen atom to which it is attached, form an optionally substituted 5-7 membered non-aromatic heterocycle;

The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, -NRCO (C ₁ -C ₄ alkyl ), -CONR (C ₁ -C ₄ alkyl), -NRCO ₂ (C ₁ -C ₄ alkyl), a C ₃ -C ₇ non-aromatic carbocycle optionally substituted with one or more J ^E1 substituents, one or more substituents 4- to 7-membered non-aromatic heterocycle optionally substituted with J ^El ; And one or more substituents independently selected from the group consisting of phenyl optionally substituted with one or more J ^El which is a substituent;

Wherein the carbocycle, heterocycle, phenyl and heteroaryl represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ Alkyl), —C (O) O (C ₁ -C ₄ alkyl) and —CO ₂ H independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cya Furnace, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ Optionally and independently substituted with one or more substituents independently selected from the group consisting of -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ Alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently C, optionally substituted with one or more substituents independently selected from the group consisting of -H, halogen, or substituents halogen, hydroxy and C ₁ -C ₆ alkoxy. _1- C ₆ alkyl.

J ^A and J ^B are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b ; Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _1- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy Optionally and independently.

n is 0 or 1;

x is 0 or 1.

The remaining letters are each independently as described in any set of letters for Formulas IA and I above.

In another embodiment, such compounds or pharmaceutically acceptable salts are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Rings G1 to G4 are each independently, a 5- to 10-membered further substituted with optionally substituted with one or more J ^A non-aromatic bridging a carbocycle, the ring G5 is a 5- substituted further optionally substituted with one or more J ^B To 10 membered non-aromatic bridged heterocycles.

X is -O-, -S- or -NR ^g- .

R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, hydroxy, C ₁ -C ₆ Alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) ( Independently from the group consisting of C ₁ -C ₆ alkyl), —NHC (O) (C ₁ -C ₆ alkyl), and —N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected.

R ^g is —H, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy.

q is 0, 1 or 2.

r is 1 or 2.

The remaining characters are each independently as described above in the previous section.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein the letters are each independently as described in the preceding sections, except for those described below:

R ¹ is -H.

R ² is -H.

R ³ is —H, —F, —Cl, C _1-4 alkyl or C _1-4 haloalkyl. Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is -H.

Z ³ is -H.

X is -O-.

R ⁵ is -H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted phenyl.

Each R ⁸ is independently —H, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl or —O ( C ₁ -C ₄ alkyl).

R ⁹ , R ¹³ and R ¹⁴ are each independently —H or C ₁ -C ₄ alkyl.

R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, hydroxy, C ₁ -C ₆ alkyl and — O a (C _1- C ₆ alkyl) group optionally substituted by C ₁ -C ₆ with one or more substituents independently selected from consisting of alkyl. Specifically, R ²¹ , R ²² , R ²³ , R ^24, and R ²⁵ are each independently —H, C _1-6 alkyl, or C _1-6 haloalkyl.

Rings G1 to G5 are each halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ Alkyl) and one or more substituents independently and optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy and C ₁ -C ₄ alkoxy and optionally substituted by one or more substituents selected from the group consisting of C ₁ -C ₄ alkyl. .

In another embodiment, the compounds are of Formulas I-V (hereafter reference to Formulas I-IV include Formulas I, IA, II, III, IV, V and VI) and Formulas XIA-XIV (hereafter References to XIA to XIV are represented by the formulas XIA, XIB, XIIA, XIIB, XIII and XIV), wherein the meanings of these letters are independently as described above in certain embodiments, provided that ³ is C _1-6 alkyl, for example methyl or ethyl.

In another embodiment, the compounds are represented by one of Formulas I-V and XIA-XIV, wherein the meanings of these letters are independently as described above in any of the foregoing embodiments, provided that x is 0 to be.

In another embodiment, the compounds are represented by any one of Formulas I, IA, II, VI, XIA and XI (B), wherein the meanings of their letters are independently as described above in any of the above-described embodiments However, ring A is bridged.

In another embodiment, the compounds are represented by any one of Formulas I, IA, II, VI, XIA and XI (B), wherein the meanings of their letters are independently as described above in any of the above-described embodiments Provided that Q ² is independently -C (= NR)-, -C (= NR) NR-, -NRC (= NR) NR-, -CO _2- , -OC (O)-, -C (O ) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or-(CR ⁶ R ⁷ ) _p -Y ^1- ; Alternatively, Q ² is independently -CO _2- , -OC (O)-, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O- , -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or-(CR ⁶ R ⁷ ) _p -Y ^1- .

In another embodiment, the compounds are represented by one of Formulas I-V and XIA-XIV, wherein the meanings of these letters are independently as described above in any of the foregoing embodiments, provided that Q ² is When -O- or -NR-, ring A is further substituted with J ^A rather than -H; Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. In certain embodiments, when Q ² is -O- or -NR-, ring A is further substituted with J ^A instead of -H at the same position relative to -Q ² R ⁵ .

In yet another aspect, the present invention is directed to FIGS. 3aa-3cd, 4a-4w, 5a-5c, 6a-6v, 7a-7h, and 8a for any of the uses described above. It relates to the use of any compound selected from the compounds shown in FIG. 8B or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are represented by any one of Formulas I-V and XIA-XIV, and the letters are each independently as shown in the compounds of FIGS.

In another embodiment, the present invention provides for any of the uses described above, embodiments of the formulas (I) to (V) and (XIA) to (XIV) as described above, wherein R ³ is -Cl and Z ¹ is When -F and Z ² is -H, R ⁴ relates to the use of a compound as described in any one of 2-NH ₂ -cyclohexyl or a pharmaceutically acceptable salt thereof.

In another embodiment, the compounds described herein or pharmaceutically acceptable salts thereof reduce viral titers in a biological sample (eg infected cell culture) or human (eg lung viral titer in a patient). Can be used.

As used herein, the terms “influenza virus mediated condition”, “influenza infection” or “influenza” may be used interchangeably to mean a disease resulting from influenza virus infection.

Influenza is an infectious disease affecting birds and mammals caused by influenza viruses. Influenza viruses are RNA viruses of the family Orthomyxoviridae , which include five genera, Influenza Virus A, Influenza Virus B, Influenza Virus C, Isavirus and Togoto Virus. The influenza virus A genus has one species, the influenza A virus, which is based on antibody responses to these viruses, different serotypes: H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7 Can be classified as Influenza Virus B genus has one species, the influenza B virus. Influenza B infects humans almost exclusively and is less common than influenza A. The influenza virus C genus has one species, the influenza virus C virus, which can infect humans and swine and cause serious diseases and local epidemics. Influenza virus C, however, is less common than other types and usually appears to cause mild disease in children.

In some embodiments of the invention, the influenza or influenza virus is associated with influenza virus A or B. In some embodiments of the invention, the influenza or influenza virus is associated with influenza virus A. In some specific embodiments of the invention, influenza virus A is H1N1, H2N2, H3N2 or H5N1.

In humans, common symptoms of influenza are chills, fever, pharyngitis, myalgia, severe headache, cough, weakness and general discomfort. In more severe cases, influenza causes pneumonia, which can be fatal, especially in children and the elderly. Although often confused with a cold, influenza is a much more serious disease and is caused by different types of viruses. Influenza can cause nausea and vomiting, especially in children, but these symptoms are more characteristic in unrelated gastroenteritis, often called "stomach flu" or "24-hour flu."

Symptoms of influenza can begin very suddenly one to two days after infection. Usually, the first symptom is chills or chills, but fever is also common early in the infection, with body temperatures ranging from 38 to 39 ° C. (approximately 100 to 103 ° F.). Many people get so sick that they can lie down for days, with pain and pain throughout the body, which is worse in the lower back and legs. Symptoms of influenza include body aches, especially pain in joints and throats, extreme cold and fever, fatigue, headaches, irritated bites, red eyes, skin (particularly face), pain in the mouth, neck and nose, abdominal pain (influenza B Children with children). Symptoms of influenza are non-specific and overlap with many pathogens (influenza-like disease). In general, laboratory data are needed to confirm the diagnosis.

As used herein, the terms "disease", "disorder" and "state" are used interchangeably and refer to influenza virus mediated medical or pathological conditions.

As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (eg birds, such as chickens, quails or turkeys, or mammals), specifically non-primates (eg cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, By "mammals" including cats, dogs and mice) and primates such as monkeys, chimpanzees and humans, more specifically humans. In one embodiment, the subject is a non-human animal such as a farm animal (eg horse, cow, pig or sheep) or a pet (eg dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a "person."

The term "biological sample" as used herein includes, without limitation, cell culture or extract thereof; Biopsied material obtained from a mammal or extracts thereof; Blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

As used herein, “multiplicity of infection” or “MOI” is the ratio of infectious component (eg, phage or virus) to infection target (eg, cell). For example, when referring to a population of cells inoculated with infectious viral particles, the multiplicity of infection or MOI is the ratio defined by the number of infectious viral particles deposited in one well divided by the number of target cells present in the well.

As used herein, the term “inhibition of influenza virus replication” includes both a decrease in the amount of viral replication (eg, a reduction of at least 10%) and complete inhibition of virus replication (ie, a 100% reduction in the amount of virus replication). do. In some embodiments, replication of the influenza virus is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90% or at least 95%.

Influenza virus replication can be measured by any suitable method known in the art. For example, influenza virus titers can be measured in biological samples (eg, infected cell cultures) or humans (eg, lung virus titers in patients). More specifically, for cell based assays, cells are incubated in each case in vitro, virus is added to the culture in the presence or absence of the test agent and the virus-dependent endpoint is assessed after a suitable length of time. For a typical assay, Madin-Darby canine kidney cells (MDCK) and influenza strains, A / Puerto Rico / 8/34, adapted to standard tissue cultures can be used. The first type of cell assay that can be used in the present invention relies on the killing of infected target cells, a process called the cytopathic effect (CPE), where viral infection is associated with depletion of cellular resources and ultimately cell lysis. Cause In the first type of cell assay, a low fraction of cells is infected (typically 1/10 to 1/1000) in the wells of a microtiter plate, followed by multiple replications of the virus over 48 to 72 hours, followed by infection. The amount of cell death is measured using a decrease in cellular ATP content relative to the non-control. The second type of cell assay that can be used in the present invention relies on the proliferation of virus-specific RNA molecules in infected cells and directly measures RNA levels using branched chain DNA hybridization (bDNA). In the second type of cell assay, a low number of cells are first infected in the wells of the microtiter plate, and within the infected cells the virus replicates and spreads to additional cells nearby, followed by lysis and viral RNA content. Measure This assay is stopped early, usually after 18 to 36 hours, but all target cells are still viable. Viral RNA is quantified by hybridizing to specific oligonucleotide probes immobilized in the wells of the assay plate and then amplifying the signal by hybridization with additional probes linked to the reporter enzyme.

As used herein, "viral titer (or titer)" is a measure of viral concentration. Activity test can use serial dilution to obtain approximate quantitative information from an analytical procedure that evaluates essentially positive or negative only. The titer still corresponds to the highest dilution factor that gives a positive determination; For example, a positive determination at the first 8 consecutive double dilutions is interpreted as a titer of 1: 256. One embodiment is viral titer. To measure the titer, several dilutions such as 10 ⁻¹ , 10 ⁻² , 10 ⁻³ , ..., 10 ⁻⁸ will be prepared. The lowest concentration of virus that still infects cells is the virus titer.

As used herein, the terms “treat”, “treatment” and “treating” mean both therapeutic and prophylactic treatment. For example, therapeutic treatment may be a reduction or alleviation of the progression, severity and / or duration of an influenza virus mediated condition resulting from the administration of one or more therapeutic agents (eg, one or more therapeutic agents such as a compound or composition of the invention), or Alleviation of one or more symptoms (specifically, one or more identifiable symptoms) of an influenza virus mediated condition. In specific embodiments, the therapeutic treatment includes alleviation of one or more measurable physical parameters of the influenza virus mediated condition. In another aspect, the therapeutic treatment comprises physically inhibiting the progression of an influenza virus mediated condition, for example by stabilizing an identifiable symptom, or physiologically, for example by stabilizing a physical parameter, or these Include both. In another embodiment, the therapeutic treatment includes reducing or stabilizing influenza virus mediated infection. Antiviral drugs can be used to treat people who already have influenza in a community setting to reduce the severity of symptoms and reduce the number of days of illness.

The term "chemotherapy" means the use of a medicament, such as a small molecule drug, rather than a "vaccine" to treat a disorder or disease.

As used herein, the terms "prophylaxis" or "prophylactic use" and "prophylactic treatment" refer to any medical or public health procedure for the purpose of prevention rather than treatment or cure of a disease. As used herein, the terms “prevent”, “prevention” and “preventing” are intended to reduce the risk of developing or developing a given condition, or are not suffering from, but may be or may be near a person suffering from a disease. Means reducing or inhibiting the recurrence of the condition. The term "chemical prophylaxis" means the use of a medicament (eg, a small molecule drug) (rather than a "vaccine") to prevent a disorder or disease.

As used herein, the prophylactic uses are places where a large number of people at high risk of serious influenza complications live in close proximity to each other (eg, hospital facilities, day care centers, prisons, nursing facilities, etc.) in the presence of a collective infection detected. And use to prevent the transmission or spread of infection. It also includes use in people who need protection from influenza but are not protected after vaccination (eg due to a weak immune system), or that the vaccine is ineffective or not receiving the vaccine due to side effects. This also includes use during the two weeks following vaccination because the vaccine is still ineffective. Prophylactic use may also include treatment to reduce the likelihood that a person who does not suffer from influenza or is not considered high risk for complications will be infected with influenza and spread to nearby high-risk people (eg, health care). Health care workers, care workers, etc.).

According to the US CDC, influenza "cold infections" occur within a group of people in close proximity to each other (e.g., in the same area of an assisted living facility, in the same home, etc.). It is defined as a sudden increase in acute febrile respiratory illness (AFRI) that occurs within a period of 48 to 72 hours when analyzed in the test for positive. One case of influenza identified by any test method is considered a population infection.

A “patient community” is defined as a group of three or more cases of AFRI that occur within a period of 48 to 72 hours within a group of people in close proximity to each other (eg, in the same area of an assisted living facility, in the same home, etc.).

As used herein, an “indicator case”, “primary case” or “patient zero” is the first patient in a population sample in epidemiological investigations. Generally, when referring to such patients in epidemiological investigations, the term is not capitalized. When the term refers to a specific person in place of a person's name in a particular research report, the term is capitalized, such as "Patient Zero." Often, scientists study indicator cases to determine how the disease spreads and what reservoirs are present between population infections. Note that the indicator case is the first patient to indicate the presence of a group infection. Earlier instances can be found, which are labeled as primary, secondary, tertiary, etc.

In one embodiment, the methods of the invention are prophylactic or "preemptive" measures for patients with predisposition to complications due to infection with the influenza virus, in particular humans. The term "preemptive" as used herein, for example, for proactive use, "preemptively," or the like, is intended to prevent the spread of infection in the rest of the community or population in situations where an "indication case" or "cold infection" has been identified. It is a preventive use.

In another embodiment, the methods of the present invention are applied as "proactive" measures against members of a community or population group, specifically people, to prevent the spread of infection.

As used herein, "effective amount" means an amount sufficient to elicit the desired biological response. In the present invention, the desired biological response inhibits the replication of influenza virus, reduces the amount of influenza virus, reduces or alleviates the severity, duration, progression or onset of influenza virus infection, or promotes the progression of influenza virus infection. Preventing, recurring, developing, developing or progressing the symptoms associated with influenza virus infection, or enhancing or improving the prophylactic therapeutic effect (s) of another therapeutic agent used for influenza infection. The exact amount of compound administered to a subject will vary depending on the mode of administration, the type and severity of the infection and the characteristics of the subject's general health, age, sex, weight and drug resistance. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. When co-administered with other antiviral agents, for example when co-administered with anti-influenza agents, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for the approved medicaments and can be adjusted by one skilled in the art depending on the condition of the subject, the type of condition (s) being treated and the amount of compound described herein. If the quantity is not explicitly stated, the effective amount should be estimated. For example, the compounds described herein can be administered to a subject at a dosage ranging from approximately 0.01 to 100 mg / kg body weight / day for therapeutic or prophylactic treatment.

In general, the dosing regimen includes the disorder to be treated and the severity of the disorder; The activity of the specific compound employed; The specific composition employed; The age, body weight, general health, sex and diet of the patient; Time of administration, route of administration, and rate of release of the specific compound employed; Kidney and liver function of the subject; And the specific compound or salt thereof used, the duration of treatment; It may be selected according to various factors including drugs used in combination or coincidental with the specific compound used, and similar factors well known in the medical arts. One skilled in the art can readily determine and prescribe an effective amount of the compounds described herein necessary to treat, prevent, inhibit (completely or partially) or retard the progression of a disease.

The dosage of the compounds described herein is about 0.01 to about 100 mg / kg body weight / day, about 0.01 to about 50 mg / kg body weight / day, about 0.1 to about 50 mg / kg body weight / Days or from about 1 to about 25 mg / kg body weight / day. The total daily dose may be administered in a single dose or multiple doses, such as twice daily (eg every 12 hours), three times daily (eg every 8 hours) or four times daily (eg every 6 hours) It is understood that it can be administered.

For therapeutic treatment, the compounds described herein, for example, within 48 hours (or 40 hours or less than 2 days) onset of symptoms (eg nasal congestion, sore throat, cough, pain, fatigue, headache and chills / perspiration) Or less than 1.5 days, or within 24 hours). The therapeutic treatment can last for a suitable period of time, such as for example 5 days, 7 days, 10 days, 14 days, and the like. For prophylactic treatment during community outbreaks, the compounds described herein can be administered to a patient, for example within 2 days of symptom onset in an index case, for example 7 days, 10 days, 14 days, For any suitable period, such as for 20 days, 28 days, 35 days, 42 days, and the like.

Various methods of administration can be used in the present invention, which are described in detail in the section entitled "How to administer".

Combination therapy

The effective amount is a compound or medicament of any one of Formulas I-V (e.g., Formulas I, IA, II, III, IV and V) and XIA-XIV (e.g., Formulas XIA, XIB, XIIA, XIIB, XIII and XIV) It can be achieved in the method or pharmaceutical composition of the present invention using a pharmaceutically acceptable salt or solvate thereof (eg hydrate) alone or in combination with additional suitable therapeutic agents such as antiviral agents or vaccines. When “combination therapy” is used, an effective amount is the first amount of a compound of any of Formulas I-V and XIA-XIV, or a pharmaceutically acceptable salt or solvate thereof, such as a hydrate, and further suitable therapeutic agents. (E.g., antiviral agents or vaccines).

In another embodiment of the invention, the compound of any one of Formulas I-V and XIA-XIV and the additional therapeutic agent are each administered in an effective amount (ie, each administered in a therapeutically effective amount when administered alone). In another embodiment, the compound of any one of Formulas I-V and XIA-XIV and the additional therapeutic agent are each administered in an amount (up to a therapeutic dose) that alone does not provide a therapeutic effect. In another embodiment, the compound of any one of Formulas I-V and XIA-XIV can be administered in an effective amount and the additional therapeutic agent is administered in an amount below the therapeutic dose. In another embodiment, the compounds of any one of Formulas I-V and XIA-XIV can be administered in amounts up to a therapeutic dose and additional therapeutic agents, such as suitable cancer-therapeutic agents, are administered in effective amounts.

As used herein, the terms “combination” or “coadministration” can be used interchangeably and mean using more than one therapeutic agent (eg, one or more prophylactic and / or therapeutic agents). The use of the terms does not limit the order in which the therapeutic agents (eg, prophylactic and / or therapeutic agents) are administered to a subject.

Co-administration administers the first and second amounts of the co-administered compounds in an essentially simultaneous manner as a single pharmaceutical composition, eg as a capsule or tablet having a proportion of the first and second amounts, or For administration as a plurality of individual capsules or tablets. In addition, such co-administration also includes the use of each compound in a sequential manner in any order.

In one embodiment, the present invention uses a compound or pharmaceutical composition of any one of Formulas I-V and XIA-XIV to inhibit flu virus replication in a biological sample or patient or to treat influenza virus infection in a patient. Or a method of combination therapy for the prevention or prevention. Accordingly, the pharmaceutical compositions of the present invention also include those comprising an inhibitor of flu virus replication of the present invention together with an antiviral compound exhibiting anti-influenza virus activity.

The method of using the compounds and compositions of the present invention may also be used in combination with a chemotherapeutic agent with a compound or composition of any one of Formulas I-V and XIA-XIV, or with a compound or composition of the invention as another antiviral agent and flu vaccine. Combination of vaccination of the drug.

If the co-administration comprises separate administration of the first amount of the compound of any one of Formulas I-V and XIA-XIV and the second amount of the additional therapeutic agent, the compounds are close enough to have the desired therapeutic effect. Is administered within. For example, the time interval between each administration that can induce the desired therapeutic effect can range from a few minutes to several hours, which is characterized by properties such as the efficacy, solubility, bioavailability, plasma half-life and kinetic profile of each compound. Can be determined in consideration of the above. For example, the compound of any one of Formulas I-V and XIA-XIV and the second therapeutic agent are within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, about 1 of each other. It may be administered in any order within hours or within about 30 minutes of each other.

More specifically, the first therapeutic agent (e.g., a prophylactic or therapeutic agent such as a compound of the invention) may be administered prior to administration of the second therapeutic agent (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to the subject (e.g., 5 minutes, 15 minutes, 30 Minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or concurrently or after administration (eg 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks later).

The method of co-administering a first amount of a compound of any one of Formulas I-V and XIA-XIV and a second amount of an additional therapeutic agent can induce an enhanced or synergistic therapeutic effect, where the combined effect is It should be appreciated that the additive effect obtained from the individual administration of the first amount of the compound of any one of V and XIA to XIV and the second amount of the additional therapeutic agent is greater.

As used herein, the term “synergistic” refers to the combination of a compound of the invention with another therapeutic agent, such as a prophylactic or therapeutic agent, which is more effective than the additive effect of the therapeutic agents. The synergistic effect of a combination of therapies (eg, a prophylactic or a combination of therapies) allows one or more therapeutic agents to be used at lower dosages and / or to administer the therapeutic agents less frequently. The ability to use a therapeutic agent (eg, a prophylactic agent or therapeutic agent) at a lower dose and / or to administer the therapeutic agent less frequently may result in the subject being treated with the subject without reducing the efficacy of the therapeutic agent in the prevention, management or treatment of the disorder. Toxicity associated with administration can be reduced. In addition, synergistic effects may lead to improved efficacy of the therapeutic agents in the prevention, management or treatment of disorders. Finally, the synergistic effect of a combination of therapeutic agents (eg, a prophylactic or combination of therapeutic agents) can avoid or reduce the negative or unwanted side effects associated with using either of the therapeutic agents alone.

For combination therapies using a compound of the invention of any one of Formulas I-V and XIA-XIV in combination with a flu vaccine, these therapeutic agents are both such that the time interval between each administration can be longer (eg, several days, Weeks or months).

The presence of a synergistic effect can be measured using a suitable method for assessing drug interactions. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)], the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926) and the median-effect equation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984). Each of the equations mentioned above can be applied with experimental data to generate corresponding graphs to help assess the effects of drug combinations. Corresponding graphs associated with the above mentioned equations are concentration-effect curves, isobologram curves and combination index curves, respectively.

Embodiments that may be co-administered with the compounds described herein include neuraminidase inhibitors such as oseltamivir (Tamiflu®) and zanamivir (Rlenza®), viral ion channel (M2 protein). Blocking agents, such as Amantadine (Symmetrel®) and Rimantadine (Flumadine®) and antiviral drugs described in WO 2003/015798, for example T- under development by Toyama Chemical of Japan. 705 (see, eg, Ruruta et al., Antiviral Reasearch, 82: 95-102 (2009), "t-705 (flavipiravir) and related compounds: a wide range of novel inhibitors of RNA virus infection"). . In some embodiments, the compounds described herein can be co-administered with conventional influenza vaccines.

Compounds of the Invention

Another aspect of the invention relates generally to compounds. In one embodiment, the present invention relates generally to compounds represented by formula (IA) or (I) or a pharmaceutically acceptable salt thereof.

Formula IA

Formula I

The first subset of letters of Formulas I and IA for the compounds of the present invention is as follows:

R ¹ is —H, C ₁ -C ₆ alkyl, —S (O) ₂ —R ″ or —C (O) OR ″. Specifically, R ¹ is -H or S (O) ₂ -R ". Specifically, R ¹ is -H or -S (O) _2- (phenyl), wherein phenyl is C ₁ -C ₆ Optionally substituted with one or more substituents selected from the group consisting of alkyl and C ₁ -C ₆ haloalkyl More specifically, phenyl is from a group consisting of —CH ₃ and —CF ₃ (eg, at its para position) Optionally substituted with one or more substituents selected, specifically, R ¹ is —H or C _1-6 alkyl, specifically R ¹ is —H.

이다.R ⁴ is

to be.

Is independently i) halogen, cyano, hydroxyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkoxy, One or more independently selected from the group consisting of C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ -alkyl optionally substituted with substituents, or ii) halogen, cyano, hydroxy, oxo, nitro, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C _2- to C ₆ alkoxyalkoxy one or more substituents independently selected from the group consisting of optionally and independently value A, C ₃ -C _6, a cyclic group, a 5- or 6-membered heteroaryl group or a phenyl group of the carbonyl. More specifically, R "is independently, optionally substituted heterocyclic 5-or 6-membered aryl group or optionally Substituted phenyl group. Specifically, R ″ is independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl.

Z ¹ , Z ² , Z ³ , Q ¹ , Q ² , Q ³ , Y ¹ , rings A to D, R ^* , R, R ', R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ^a , R ^b , R ^c , R ^d , J ^A , J ^B , J ^C1 , J ^D1 and J ^E1 mean, Each independently as described above in the first set of letters of formulas IA and I for the method of the present invention, including the specific meanings and substituents thereof.

p meaning is independently 1, 2, 3 or 4. Specifically, p is 1 or 2 independently.

When rings A and B are 3 to 6 members, n and m are each independently 0 or 1; k is independently 0, 1 or 2. Alternatively, when rings A and B are 7-10 membered, n and m are each independently 0, 1 or 2; k is independently 0, 1 or 2.

The x and y meanings are each independently 0, 1 or 2.

z means 1 or 2.

Provided that when Y ¹ is a bond, R ⁵ is neither -H nor an unsubstituted C ₁ -C ₆ aliphatic group. Specifically, when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. Specifically, a C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ N (R) R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NRR ^b independently; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. Specifically, when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Or an optionally substituted 4-8 membered non-aromatic heterocycle.

)이 아니다.Alternatively, ring A and B are each independently 5- or 6-membered, R ¹ and R ² are both -H, R ³ is -Cl, Z ² is -H, and Z ¹ is -F When Q ² -R ⁵ and Q ³ -R ⁵ are each not -H; However, ring BQ ³ -R ⁵ residue is N-methyl-3-pyrrolidinyl (

Not)

The second subset of letters of formulas IA and I for the compounds of the present invention is as follows:

R ² is -H or -CH ₃ .

R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl) Or -N (C ₁ -C ₄ alkyl) ₂ .

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of formulas IA and I are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The third subset of letters of formula (I) for the compounds of the present invention is as follows:

R ² is -H or -CH ₃ .

R ³ is —H, —F, —Cl, —CF ₃ , —NH ₂ , —NH (CH ₃ ) or —N (CH ₃ ) ₂ .

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of formulas IA and I are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The fourth subset of letters of formulas IA and I for the compounds of the present invention is as follows:

R ² is -H or -CH ₃ .

R ³ is -H, -F or -Cl.

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of formulas IA and I are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The fifth subset of letters of formulas IA and I for the compounds of the present invention is as follows:

R ² is -H.

R ³ is -H or -Cl.

R ⁴ is selected from the formulas A to D shown above.

The meanings of the remaining letters of formulas IA and I are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The sixth subset of the letters of formulas IA and I for the compounds of the present invention are as follows:

R ² , R ³ and R ⁴ are each independently as described in the first subset, second subset, third subset, fourth subset or fifth subset of letters of Formulas IA and I.

Z ¹ is —H, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —F, —Cl, —CN, —CO ₂ H, —CO ₂ (C ₁ -C ₆ alkyl), -CONH ₂ , -CONH (C ₁ -C ₆ alkyl) or -CON (C ₁ -C ₆ alkyl) ₂ ; Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ego; Wherein said alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —CO ₂ (C ₁ -C ₆ alkyl), —NH (C ₁ -C ₆ alkyl) And alkyl groups represented by -N (C ₁ -C ₆ alkyl) ₂ ) optionally and independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C _1- C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are substituted with one or more substituents independently selected from the group consisting of.

The meanings of the remaining letters of formulas IA and I are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The seventh subset of the letters of formulas IA and I for the compounds of the present invention are as follows:

R ² , R ³ and R ⁴ are each independently as described in the first subset, second subset, third subset, fourth subset or fifth subset of letters of Formulas IA and I.

Z ¹ is -H, -F, -Cl, -CF ₃ , C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl) or -CN; Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ Wherein the alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —NH (C ₁ -C ₆ alkyl) and —N (C ₁ -C ₆ alkyl) And alkyl groups represented by ₂ ) are each optionally and independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C _1- Substituted with one or more substituents independently selected from the group consisting of C ₄ alkoxy.

The meanings of the remaining letters of formulas IA and I, as well as the specific meanings, are each independently as described in the first subset of letters.

An eighth subset of the letters of the formulas IA and I for the compounds of the present invention is as follows:

R ² , R ³ and R ⁴ are each independently as described in the first subset, second subset, third subset, fourth subset or fifth subset of letters of Formulas IA and I.

Z ¹ is —H, —F, —Cl, C ₁ -C ₄ haloalkyl (eg —CF ₃ ), C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl) or —CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

The meanings of the remaining letters of formulas IA and I, as well as the specific meanings, are each independently as described in the first subset of letters.

A ninth subset of the letters of formulas IA and I for the compounds of the present invention are as follows:

R ² , R ³ and R ⁴ are each independently as described in the first subset, second subset, third subset, fourth subset or fifth subset of letters of Formulas IA and I.

Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

The meanings of the remaining letters of formulas IA and I are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

In the tenth subset of the letters of the formulas IA and I for the compounds of the invention, the letters of the formulas IA and I, including their specific meanings, are each independently the first and second of the letters of the formulas IA and I As described in the third, fourth, fifth, sixth, seventh, eighth or ninth subsets; If applicable,

Each R ^* is independently: i) -H; ii) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C _{4 alkyl), -CO 2 H, -CO 2} (C 1 -C 4 alkyl) and C ₁ -C ₄ alkoxy optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ alkyl; Or iii) halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl) , Independently selected from the group consisting of -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy and C ₁ -C ₆ alkyl A 3-7 membered carbocyclic ring optionally substituted with the above substituents, wherein each alkyl is independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) And one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy;

R and R 'are each independently -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ and -O with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) optionally substituted C ₁ -C ₆ alkyl; Optionally, R ', together with R ⁵ and the nitrogen atom to which they are attached, form a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with one or more J ^D1 ;

R ″ is independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl.

In an eleventh subset of the letters of the formulas IA and I for the compounds of the invention, the letters of the formulas IA and I, including their specific meanings, are each independently the first and second of the letters of the formulas IA and I As described in the third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth subset; If applicable,

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the twelfth subset of the letters of the formulas IA and I for the compounds of the invention, the letters of the formulas IA and I are each independently included in the eleventh subset of the letters of the formulas IA and I, including As described;

A C ₁ -C ₆ aliphatic group, represented by R ⁵ , is substituted with one or more J ^C1 when Y ¹ is a bond, wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

The thirteenth subset of the letters of formulas IA and I are as follows:

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B , together with the atom (s) to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is Optionally substituted with one or more J ^E1 .

Q ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR'-,- C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR '-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO _2- , or -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b and -NRSO ₂ NR ^c R ^b , or, optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, are attached And independently form a 5 to 7 membered ring to be fused to each ring to which it is optionally substituted with one or more J ^E1 .

Meaning of the remaining letters of the formulas (IA) and (I), including the specific meaning, each independently of the first, second, third, fourth, fifth, sixth, seventh, fifth, of the letters of the formulas (IA) and (I) As described in the 8th, 9th, 10th, 11th or 12th subset.

In the fourteenth subset of the letters of formulas IA and I, the meanings of the letters are independently as described in the seventeenth set of letters of formulas IA and I above.

In a fifteenth subset of the letters of formulas IA and I, the meanings of the letters are independently as described in the eighteenth set of letters of formulas IA and I above.

In the sixteenth subset of the letters of formulas IA and I, the meanings of the letters are independently as described in the nineteenth set of letters of formulas IA and I above.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein R ¹ is —H or C _1-6 alkyl, and the meaning of the remaining letters is independently of the above Formulas IA and I As described in any one of the subsets of

In another embodiment, the invention relates generally to compounds represented by Formula VI or pharmaceutically acceptable salts thereof.

Formula VI

The first subset of letters of formula VI for the compounds of the present invention is as follows:

Z ¹ is —H, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —F, —Cl, —CN, —CO ₂ H, —CO ₂ (C ₁ -C ₆ alkyl), -CONH ₂ , -CONH (C ₁ -C ₆ alkyl) or -CON (C ₁ -C ₆ alkyl) ₂ , wherein said alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁₎ Alkyl groups represented by -C ₆ alkyl), -CO ₂ (C ₁ -C ₆ alkyl), -CONH (C ₁ -C ₆ alkyl) and -CON (C ₁ -C ₆ alkyl) ₂ ) are each optionally and Independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C _One- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more independently selected from the group consisting of C ₁ -C ₄ alkoxy Substituted with a substituent.

Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ Wherein the alkyl groups (eg, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —NH (C ₁ -C ₆ alkyl) and —N (C ₁ -C ₆ alkyl) And alkyl groups represented by ₂ ) are each optionally and independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C _1- Substituted with one or more substituents independently selected from the group consisting of C ₄ alkoxy.

The meanings of the remaining letters of formula VI, including the specific meanings, are each independently as described in the first subset of letters of formulas IA and I above.

The second subset of letters of formula VI for the compounds of the present invention is as follows:

Z ¹ is —H, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —F, —Cl, —CN, —CO ₂ H, —CO ₂ (C ₁ -C ₆ alkyl), -CONH ₂ , -CONH (C ₁ -C ₆ alkyl) or -CON (C ₁ -C ₆ alkyl) ₂ , wherein said alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ Alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl) , -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents independently selected from the group consisting of.

Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ego; Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected.

R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl) Or -N (C ₁ -C ₄ alkyl) ₂ .

The meanings of the remaining letters of formula VI, including the specific meanings, are each independently as described in the first subset of letters of formulas IA and I above.

The third subset of letters of formula VI for the compounds of the present invention is as follows:

Z ¹ is —H, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), —F, —Cl, —CN, —CO ₂ H, —CO ₂ (C ₁ -C ₆ alkyl), -CONH ₂ , -CONH (C ₁ -C ₆ alkyl) or -CON (C ₁ -C ₆ alkyl) ₂ , wherein said alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ Alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl) , -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents independently selected from the group consisting of.

Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ ego; Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected.

R ³ is —H, —F, —Cl, —CF ₃ , —NH ₂ , —NH (CH ₃ ) or —N (CH ₃ ) ₂ . Specifically, R ³ is -H, -Cl or -F. Specifically, R ³ is Cl.

The meanings of the remaining letters of formula VI, including the specific meanings, are each independently as described in the first subset of letters of formulas IA and I above.

In a fourth subset of the letters of formula VI for the compounds of the invention, the meanings of the letters of formula VI, including the specific meanings, are each independently described in the first subset of letters of formulas IA and I. As shown.

In a fifth subset of the letters of formula VI for the compounds of the present invention, the meanings of the letters of formula VI, including the specific meanings, are each independently the first, second, or second characters of the letters of formulas IA and I. As described in the third or fourth subset; If applicable,

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A , rather than -H;

Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the sixth subset of the letters of the formula VI for the compounds of the present invention, the meanings of the letters of the formula VI are each independently as described in the fifth subset above, including the specific meanings;

The C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 when Q ³ is —C (O) — wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle ; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In the seventh subset of the letters of the formula VI for the compounds of the invention, the meanings of the letters of the formula VI, including the specific meanings, are each independently the first, second, or second characters of the letters of the formulas IA and I. As described in the third or fourth subset; If applicable,

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the eighth subset of the letters of formula VI for the compounds of the present invention, the meanings of the letters of formula VI, including the specific meanings, are each independently described in the seventh subset of letters of formulas IA and I. As;

A C ₁ -C ₆ aliphatic group, represented by R ⁵ , is substituted with one or more J ^C1 when Y ¹ is a bond, wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In the ninth subset of the letters of the formula VI for the compounds of the present invention, the meanings of the letters of the formula VI, including the specific meanings, are each independently the first, second, or second of the letters of the formulas IA and I. As described in the third or fourth subset; If applicable,

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A , rather than -H;

Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the tenth subset of the letters of the formula (VI) for the compounds of the invention, the meanings of the letters of the formula (VI), including the specific meanings, are each independently described in the ninth subset of the letters of the formulas (IA) and (I). As;

When Q ³ is -C (O)-or Y ¹ is a bond, the C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is optionally substituted C ₃ -C ₈ Non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In the eleventh subset of letters of formula VI, the meanings of the letters of formula VI are each independently as described in the thirteenth subset of letters of formulas IA and I, including specific meanings.

In another embodiment, the invention relates generally to compounds represented by any of Formulas II, III, IV, and V, or a pharmaceutically acceptable salt thereof:

Formula II

Formula III

Formula IV

Formula V

The first subset of letters of formulas II, III, IV and V for the compounds of the present invention is as follows:

Q ² are each independently —O—, —S—, —NR′—, —C (O) —, —CO ₂ —, —OC (O) —, —C (O) NR′—, —C ( O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'- , -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Q ³ are each independently -C (O)-, -CO _2- , -C (O) NR'-, -SO _{2- ,} -SO ₂ NR'-, -C (O) NRC (O) O- Or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Z ¹ is —H, —F, —Cl, C ₁ -C ₄ haloalkyl (eg —CF ₃ ), C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl) or —CN.

Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group.

R ³ is —H, —Cl, —F, —Br, —CN, —CF ₃ , —O (C ₁ -C ₄ alkyl), —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl) Or -N (C ₁ -C ₄ alkyl) ₂ . Specifically, R ³ is -H, -F, -Cl, -CF ₃ , -NH ₂ , -NH (CH ₃ ) or -N (CH ₃ ) ₂ . Specifically, R ³ is -H, -Cl or -F. Specifically, R ³ is -Cl.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The definitions of rings A to D of formulas (II) to (V) are as defined in the first set of letters of formulas (IA) and (I), each independently including specific characters, wherein rings A to D are each optionally and independently Substituted 4 to 7 membered ring.

The meanings of the remaining letters of the formulas (II) to (V) are the same as described in the first subset of letters of formulas (IA) and (I), each independently including the specific meaning.

The second subset of letters of formulas II, III, IV and V for the compounds of the present invention is as follows:

Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

The meanings of the remaining letters of the formulas (II) to (V), including the specific meanings, are each independently as described in the first subset of letters of formulas (II) to (V).

The third subset of letters of formulas II, III, IV and V for the compounds of the present invention is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

The meanings of the remaining letters of the formulas (II) to (V), including the specific meanings, are each independently as described in the first subset of letters of formulas (II) to (V).

The fourth subset of letters of Formulas II, III, IV and V for the compounds of the present invention is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

R ³ is -H, -Cl or -F.

The meanings of the remaining letters of the formulas (II) to (V), including the specific meanings, are each independently as described in the first subset of letters of formulas (II) to (V).

The fifth subset of letters of Formulas II, III, IV, and V for the compounds of the present invention is as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

R ³ is —H, —Cl, —F, —CF ₃ , —NH ₂ , —NH (CH ₃ ) or —N (CH ₃ ) ₂ .

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

The meanings of the remaining letters of the formulas (II) to (V), including the specific meanings, are each independently as described in the first subset of letters of formulas (II) to (V).

A sixth subset of the letters of formulas II, III, IV, and V for the compounds of the present invention are as follows:

Z ¹ is -H, -F or -CN.

Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

R ³ is -H, -Cl or -F.

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

The meanings of the remaining letters of the formulas (II) to (V), including the specific meanings, are each independently as described in the first subset of letters of formulas (II) to (V).

In the seventh subset of the letters of formulas II to V for the compounds of the present invention, the meanings of the letters of formulas II to V are R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , R ¹³ And R ¹⁴ , except for R ¹⁴ , are each independently as defined in the first, second, third or fourth subsets of Formulas IA and I above.

R ⁶ and R ⁷ are each independently —H or —C ₁ -C ₄ alkyl, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —C ₁ -C ₄ alkyl.

R ¹¹ and R ¹² are each independently —H or —C ₁ -C ₄ alkyl.

R ¹³ and R ¹⁴ are each independently —H or —C ₁ -C ₄ alkyl, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

In an eighth subset of the letters of the formulas (II) to (V) for the compounds of the invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, are each independently the first subsection of the letters of the formulas (IA) and (I). As described in the set.

In the ninth subset of the letters of the formulas (II) to (V) for the compounds of the present invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, are each independently the first and second of the above formulas (II) to (V). As described in the third, fourth, fifth, sixth, seventh or eighth subset; If applicable,

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A , rather than -H;

Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the tenth subset of the letters of the formulas (II) to (V) for the compounds of the present invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, are each independently the ninth subsection of the letters of the formulas (II) to (V). As described in the set; If applicable,

When Q ³ is -C (O)-, the C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In the eleventh subset of the letters of the formulas (II) to (V) for the compounds of the present invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, are each independently the first and second of the above formulas (II) to (V). As described in the third, fourth, fifth, sixth, seventh or eighth subset; If applicable,

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the twelfth subset of the letters of the formulas (II) to (V) for the compounds of the invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, are each independently the eleventh subsection of the letters of the formulas (II) to (V). As described in the set; If applicable,

When Y ¹ is a bond, the C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In a thirteenth subset of the letters of the formulas (II) to (V) for the compounds of the present invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, are each independently the first and second of the above formulas (II) to (V). As described in the third, fourth, fifth, sixth, seventh or eighth subset; If applicable,

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A , rather than -H;

Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ² and Q ³ are each independently a bond, R ⁵ is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the fourteenth subset of the letters of the formulas (II) to (V) for the compounds of the invention, the meanings of the letters of the formulas (II) to (V), including the specific meanings, each independently of the thirteenth sub As described in the set; If applicable,

When Q ³ is -C (O)-or Y ¹ is a bond, the C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is optionally substituted C ₃ -C ₈ Non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

A fifteenth subset of the letters of Formulas II-V is as follows:

J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo and Q ¹ -R ⁵ ; Optionally, two J ^A and two J ^B , together with the atom (s) to which they are attached, each independently represent a 5-7 membered ring which is optionally substituted with one or more J ^E1 and fused to the ring to which they are attached To form.

Q ¹ is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR-, -C ( O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-,- S (O) —, —SO ₂ —, —N (R) SO ₂ —, —SO ₂ N (R) —, —NRSO ₂ NR— or — (CR ⁶ R ⁷ ) _p -Y ^1- .

Q ² is independently a bond, -O-, -S-, -NR-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR-, -C ( O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-,- S (O) —, —SO ₂ —, —N (R) SO ₂ —, —SO ₂ N (R) —, —NRSO ₂ NR— or — (CR ⁶ R ⁷ ) _p -Y ^1- .

Q ³ is, independently, a bond, -C (O)-, -CO _2- , -C (O) NR-, -SO _{2- ,} -SO ₂ N (R)-, -C (O) NRC (O ) O- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

R ⁵ is i) -H; ii) a C ₁ -C ₆ aliphatic group optionally substituted with one or more J ^C1 ; iii) a C ₃ -C ₈ non-aromatic carbocycle or a 6 to 10 membered carbocyclic aryl group, each optionally and independently substituted with one or more J ^C1 ; Or iv) a 4-8 membered non-aromatic heterocycle or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more J ^D1 .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C (O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b and -NRSO ₂ NR ^c R ^b , or, optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, are attached And independently form a 5 to 7 membered ring to be fused to each ring to which it is optionally substituted with one or more J ^E1 .

Ring A is a C ₃ -C ₈ non-aromatic carbocycle optionally and independently further substituted with one or more J ^A.

Meaning of the remaining characters of the formula (II) to V, including the specific meaning, each independently of the first, second, third, fourth, fifth, sixth, seventh, fifth, of the characters of the formula (II) As described in the eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth subsets.

In another embodiment, the present invention generally relates to compounds of formula XIA or XIB or pharmaceutically acceptable salts thereof.

Chemical Formula XIA

Formula XIB

The first subset of letters of formulas XIA and XIB for the compounds of the present invention is as follows:

Q ² are each independently —O—, —S—, —NR′—, —C (O) —, —CO ₂ —, —OC (O) —, —C (O) NR′—, —C ( O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'- , -SO _2- , -N (R) SO _2- , -SO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N 5- to 7-membered non-substituted optionally further substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Aromatic carbocyclic ring; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of: Specifically, ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), One independently selected from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) A 5- to 7-membered non-aromatic carbocyclic ring optionally further substituted with any of the above substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H , -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents independently selected from the group consisting of. Specifically, ring A is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, 5- to 7-membered carbocyclic rings optionally further substituted with one or more substituents independently selected from the group consisting of C ₂ -C ₄ alkoxyalkoxy, -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) to be.

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

Each R ⁸ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

Each R ⁹ is independently —H or —CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A rather than -H.

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

A second subset of the letters of the formulas XIA and XIB for the compounds of the invention is as follows:

Ring A, Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the first subset of letters of the formulas XIA and XIB above.

The variable x is 0 or 1 and the variable n is 0 or 1.

The meanings of the remaining letters of formula XIA or XIB are the same as described in the first subset of letters of formulas XIA and XIB, each independently including the specific meaning.

The third subset of letters of the formulas XIA and XIB for the compounds of the present invention is as follows:

Ring A, R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the second subset of letters of the formulas XIA and XIB above.

Q ² is -O-, -NR'-, -CO-, -CO _2- , -C (O) NR'-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OCONR'-, -NRSO _2- , -SO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Specifically, Q ² is -O-, -NH-, -N (CH ₃ )-, -C (O)-, -CO _2- , -C (O) NH-, -C (O) N ( CH ₃ )-, -NHC (O)-, -N (CH ₃ ) C (O)-, -NHC (O) NR'-, -N (CH ₃ ) C (O) NR'-, -NHCO ₂ -, -N (CH ₃ ) CO _2- , -OC (O) NR'-, -NHSO _2- , -N (CH ₃ ) SO _2- , -SO ₂ NH-, -SO ₂ N (CH ₃ ) -Or-(CR ⁶ R ⁷ ) _p -Y ^1- .

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

A fourth subset of the letters of the formulas XIA and XIB for the compounds of the present invention is as follows:

Ring A, Q ² , R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the third subset of letters of the formulas XIA and XIB above.

R ⁵ is independently i) -H; ii) C ₁ -C ₆ aliphatic groups optionally substituted with one or more J ^C1 (eg, C ₁ -C ₆ -alkyl or C ₂ -C ₆ alkenyl groups); iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 .

^{C1 D1} J and J are each independently halogen, cyano, ^{oxo, R a, -OR b, -SR} b, -S (O) R a -, -SO 2 R a, -NHR c, -C ( O) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b , -OCONHR ^c , -NHC (O) NHC (O) OR ^b , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b ,- C (O) N (CH ₃ ) CO ₂ R ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and -N (CH ₃ ) SO ₂ R ^b .

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The fifth subset of letters of formulas XIA and XIB for the compounds of the present invention is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the fourth subset of letters of the formulas XIA and XIB above.

Ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C Optionally substituted with one or more substituents independently selected from the group consisting of ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Further substituted, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C _1- C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ Optionally and independently substituted with one or more substituents independently selected from the group consisting of alkoxy.

Provided that when Q ² -R ⁵ is -OR ⁵ or -NR'R ⁵ , ring A is further substituted with one or more J ^A rather than -H.

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

A sixth subset of the letters of the formulas XIA and XIB for the compounds of the present invention are as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the fifth subset of letters of formulas XIA and XIB above.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

Wherein Rings A1 to A27 are each independently optionally further substituted with one or more substituents. Specifically, rings A5, A6, A21, A24 and A26 are each independently substituted with one or more substituents other than -H. Suitable substituents are as described for ring A in the first subset of letters of formulas XIA and XIB, above.

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The seventh subset of the letters of the formulas XIA and XIB for the compounds of the present invention are as follows:

Group-[CR ¹³ R ¹⁴ ] _x -ring AQ ² -R ⁵ , ring A, Q ² , R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the sixth subset of letters of the formulas XIA and XIB above.

Each R ⁵ is independently i) -H; ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), Optionally with one or more substituents independently selected from the group consisting of —CO ₂ H, C ₃ -C ₈ non-aromatic carbocycles, phenyl, 4- to 8-membered non-aromatic heterocycles and 5- or 6-membered heteroaryls Substituted C ₁ -C ₆ -aliphatic groups; Or iii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ C ₃ -C ₇ non-aromatic carbocycle, 4- to 7-membered non-aromatic heterocycle, phenyl group, optionally and independently substituted with one or more substituents independently selected from the group consisting of alkyl) and -CO ₂ H Or a 5 or 6 membered heteroaryl ring; Wherein the alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R ⁵ are halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ −) C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy optionally and independently substituted with one or more substituents independently selected from the group consisting of; The carbocycle, phenyl, heterocycle and heteroaryl for the substituents of the C ₁ -C ₆ -aliphatic group represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ Independently and optionally substituted with one or more substituents independently selected from the group consisting of H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

An eighth subset of the letters of the formulas XIA and XIB for the compounds of the present invention is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the seventh subset of the letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

Wherein the rings A6, A8, A11, A14 and A15 are each optionally and independently substituted. Suitable substituents are as described for ring A in the first subset of letters of formulas XIA and XIB, above.

Each R ⁸ is independently halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

A ninth subset of the letters of the formulas XIA and XIB for the compounds of the present invention are as follows:

Group-[CR ¹³ R ¹⁴ ] _x -ring AQ ² -R ⁵ , ring A, Q ² , R, R ', R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the eighth subset of letters of formulas XIA and XIB, above.

Each R ⁵ is independently i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or iv) an optionally substituted 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ Alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₇ non-aromatic carbocycle and optionally substituted one or more substituents independently selected from the group consisting of 4 to 7 membered non-aromatic heterocycles. Is substituted. Wherein the carbocycle and heterocycle represented by R ^5, and R ⁵ wherein the C ₁ of the carbocycle and the heterocycle mentioned for the substituent -C ₆ alkyl group represented by each, halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) One independently selected from the group consisting of (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), and -CO ₂ H Independently and optionally substituted with one or more substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of:

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The tenth subset of the letters of the formulas XIA and XIB for the compounds of the present invention is as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the seventh subset of the letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

Wherein the rings A1 to A4, A7 to A20, A22, A23, A25 and A27 are each optionally and independently substituted. Suitable substituents are as described for ring A in the first subset of letters of formulas XIA and XIB, above.

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

The eleventh subset of the letters of the formulas XIA and XIB for the compounds of the present invention are as follows:

Q ² , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ , x and n, including the specific meanings, are each independently as described in the seventh subset of the letters of the formulas XIA and XIB.

Group-[(C) _0-1 R ¹³ R ¹⁴ ] -ring AQ ² -R ⁵ is independently selected from one of the following:

Wherein rings A5 to A7, A21, A24 and A26 are each optionally further and independently substituted. Suitable substituents are as described for ring A in the first subset of letters of formulas XIA and XIB, above.

Each R ⁸ is independently halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

The meanings of the remaining letters of formulas XIA and XIB are the same as described in the first subset of letters of formulas IA and I, each independently, including specific meanings.

In the twelfth subset of the letters of the formulas XIA and XIB for the compounds of the invention, the meanings of the letters of the formulas XIA and XIB, including their specific meanings, are each independently the first subsection of the letters of the formulas IA and I As described in the set.

In a thirteenth subset of the characters of formulas XIA and XIB for the compounds of the present invention, the meanings of the characters of formulas XIA and XIB, including the specific meanings, are each independently of the first, As described in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subsets; If applicable,

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ² is a bond, R ⁵ is optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the fourteenth subset of the characters of the formulas XIA and XIB for the compounds of the invention, the meanings of the characters of the formulas XIA and XIB, including the specific meanings, are each independently the thirteenth subsection of the characters of the formulas XIA and XIB. As described in the set; If applicable,

When Y ¹ is a bond, the C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In a fifteenth subset of the characters of formulas XIA and XIB, the meanings of the characters of formulas XIA and XIB, including the specific meaning, each independently of the thirteenth subset of the characters of formulas IA and I, of the characters of formula VI As described in the eleventh subset or in the fifteenth subset of the letters II through V.

In another embodiment, the present invention generally relates to compounds of Formula XIIA or XIIB or pharmaceutically acceptable salts thereof.

Formula XIIA

Formula XIIB

The first subset of letters of formulas XIIA and XIIB for the compounds of the present invention is as follows:

Q ³ are each independently -C (O)-, -CO _2- , -C (O) NR'-, -SO _2- , -SO ₂ NR'-, -C (O) NRC (O) O- Or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Ring B is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N 4- to 7-membered non-optionally further substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Aromatic heterocyclic ring; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of: Specifically, ring B is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), One independently selected from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl) -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl) Optionally further substituted with the above substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C Optionally and independently substituted with one or more substituents independently selected from the group consisting of _1- C ₄ alkoxy. Specifically, ring B is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, Optionally further substituted with one or more substituents independently selected from the group consisting of C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H and —CO ₂ (C ₁ -C ₄ alkyl).

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R ⁹ is -H or -CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. Specifically, said C ₁ -C ₆ aliphatic group is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

The second subset of the letters of the formulas XIIA and XIIB for the compounds of the present invention are as follows:

Ring B, Q ³ , R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the first subset of letters of formulas XIIA and XIIB above.

The variable y is zero or one.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

The third subset of letters of formulas XIIA and XIIB is as follows:

Ring B, R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the second subset of letters of formulas XIIA and XIIB above.

Q ³ is independently -C (O)-, -CO _2- , -C (O) NH-, -C (O) N (CH ₃ )-, -C (O) NHC (O) O-,- C (O) N (CH ₃ ) C (O) O-, -SO _2- , -SO ₂ NH-, -SO ₂ N (CH ₃ )-or-(CR ⁶ R ⁷ ) _p -Y ^1- .

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

The fourth subset of letters of formulas XIIA and XIIB for the compounds of the present invention is as follows:

Ring B, Q ³ , R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the third subset of letters of formulas XIIA and XIIB above.

R ⁵ is independently i) -H; ii) a ^C1 to one or more of J, optionally substituted C ₁ -C ₆ aliphatic group (for example: C ₁ -C ₆ - alkyl, C ₂ -C ₆ - alkenyl group); iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 .

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NHR ^c , -C (O ) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b , -OCONHR ^c , -NHC (O) NHC (O) OR ^b , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b , -C (O) N (CH ₃ ) CO ₂ R ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and —N (CH ₃ ) SO ₂ R ^b .

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

The fifth subset of letters of formulas XIIA and XIIB for the compounds of the present invention is as follows:

Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the fourth subset of letters of formulas XIIA and XIIB, above.

Ring B is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C Optionally substituted with one or more substituents independently selected from the group consisting of ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Further substituted, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ ,- Independently from the group consisting of OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents selected.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

The sixth subset of the letters of the formulas XIIA and XIIB for the compounds of the present invention is as follows:

Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the fifth subset of letters of formulas XIIA and XIIB above.

Ring B is independently selected from one of the following structures:

Wherein the rings B1, B2 and B4 to B9 are each optionally and independently substituted. Suitable substituents are independently as described for ring B in the first subset of letters of formulas IA and I above.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

The seventh subset of the letters of the formulas XIIA and XIIB for the compounds of the invention is as follows:

Ring B, Q ³ , R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the sixth subset of letters of the formulas XIIA and XIIB above.

Each R ⁵ is independently i) -H; ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), Optionally with one or more substituents independently selected from the group consisting of —CO ₂ H, C ₃ -C ₈ non-aromatic carbocycles, phenyl, 4- to 8-membered non-aromatic heterocycles and 5- or 6-membered heteroaryls Substituted C ₁ -C ₆ -aliphatic groups; Or iii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ C ₃ -C ₇ non-aromatic carbocycle, 4- to 7-membered non-aromatic heterocycle, phenyl group, optionally and independently substituted with one or more substituents independently selected from the group consisting of alkyl) and -CO ₂ H Or a 5 or 6 membered heteroaryl ring; Wherein the alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R ⁵ are halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ −) C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy optionally and independently substituted with one or more substituents independently selected from the group consisting of; The carbocycle, phenyl, heterocycle and heteroaryl for the substituents of the C ₁ -C ₆ -aliphatic group represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ Independently and optionally substituted with one or more substituents independently selected from the group consisting of H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

An eighth subset of the letters of the formulas XIIA and XIIB for the compounds of the present invention is as follows:

Q ³ , R, R ', R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the seventh subset of the letters of formulas XIIA and XIIB above.

이고;Group-[C (R ¹³ R ¹⁴ )] _x -ring BQ ² -R ⁵ is

ego;

Wherein ring B2 is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, C ₂ -C ₄ alkoxycarbonyl, -CO ₂ H is replaced by -CO ₂ and optionally with one or more substituents independently selected from the group consisting of (C ₁ -C ₄ alkyl) and independently added.

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

A ninth subset of the letters of the formulas XIIA and XIIB for the compounds of the present invention are as follows:

Ring B, Q ³ , R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ , The meanings of R ¹² , R ¹³ , R ¹⁴ and y, including the specific meanings, are each independently as described in the eighth subset of letters of the formulas XIIA and XIIB above.

Each R ⁵ is independently i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or iv) an optionally substituted 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ Alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₇ non-aromatic carbocycle and optionally substituted one or more substituents independently selected from the group consisting of 4 to 7 membered non-aromatic heterocycles. Is substituted. Wherein the carbocycle and heterocycle represented by R ^5, and R ⁵ wherein the C ₁ of the carbocycle and the heterocycle mentioned for the substituent -C ₆ alkyl group represented by each, halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) One independently selected from the group consisting of (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), and -CO ₂ H Independently and optionally substituted with one or more substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of:

The meanings of the remaining letters of the formulas XIIA and XIIB are the same as described in the first subset of letters of formulas IA and I, respectively, independently including the specific meanings.

In the tenth subset of the letters of the formulas XIIA and XIIB for the compounds of the invention, the meanings of the letters of the formulas XIIA and XIIB, including the specific meanings, are each independently the first subsection of the letters of the formulas IA and I As described in the set.

In the eleventh subset of the letters of the formulas XIIA and XIIB for the compounds of the invention, the meanings of the letters of the formulas XIIA and XIIB, including the specific meanings, each independently of the first, As described in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subsets; If applicable,

Provided that when Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group;

Provided that when Q ³ is a bond, R ⁵ is optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group.

In the twelfth subset of the letters of the formulas XIIA and XIIB for the compounds of the invention, the meanings of the letters of the formulas XIIA and XIIB, including their specific meanings, are each independently the eleventh subsection of the letters of the formulas As described in the set; If applicable,

When Y ¹ is a bond, the C ₁ -C ₆ aliphatic group represented by R ⁵ is substituted with one or more J ^C1 , wherein J ^C1 is an optionally substituted C ₃ -C ₈ non-aromatic carbocycle; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Optionally substituted 5-10 membered heteroaryl groups; -OR ^b ; -SR ^b ; -S (O) R ^a ; -SO ₂ R ^a ; -NR ^b R ^c ; -C (O) R ^b ; -C (O) OR ^b ; -OC (O) R ^b ; -NRC (O) R ^b ; -C (O) NR ^b R ^c ; -NRC (O) NR ^b R ^c ; -NRC (O) OR ^b ; -OCONR ^b R ^c ; -C (O) NRCO ₂ R ^b ; -NRC (O) NRCO ₂ R ^b ; -C (O) NR (OR ^b ); -SO ₂ NR ^c R ^b ; -NRSO ₂ R ^b ; And -NRSO ₂ NR ^c R ^b ; Optionally, two J ^C1 and two J ^D1 , together with the atoms to which they are attached, independently form a five to seven membered ring that is fused to each ring to which they are attached, wherein the ring is one or more Optionally substituted with J ^E1 .

In the thirteenth subset of the characters of formulas XIIA and XIIB, the meanings of the characters of formulas XIIA and XIIB, including the specific meaning, each independently of the thirteenth subset of the characters of formulas IA and I, of the characters of formula IV As described in the eleventh subset or in the fifteenth subset of the letters II through V.

In another embodiment, the present invention relates generally to compounds of Formula (XIII) or pharmaceutically acceptable salts thereof:

Formula XIII

The first subset of letters of formula XIII for the compounds of the invention is as follows:

Ring C is halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl ) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C 5- to 7-membered non-aromatic hetero optionally substituted with one or more substituents independently selected from the group consisting of _1- C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Cyclic rings; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO ( One independently selected from the group consisting of C ₁ -C ₄ alkyl), —CO (C ₁ -C ₄ alkyl), —CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with the above substituents. Specifically, ring C is halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N One or more substituents independently selected from the group consisting of (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Optionally further substituted, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected. Specifically, ring C is halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, is substituted with -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl), optionally added with one or more substituents independently selected from the group consisting of.

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R ⁹ is -H or -CH ₃ .

R ¹¹ and R ¹² are each independently —H or —CH ₃ .

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The meanings of the remaining letters of formula (XIII), including the specific meanings, are each independently as described in the first subset of letters of formulas (IA) and (I) above.

The second subset of letters of formula XIII for the compounds of the present invention is as follows:

The meanings of rings C, R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹¹ and R ¹² , including the specific meanings, are each independently as described in the first subset of letters of formula XIII above .

R ¹⁰ is —H or C ₁ -C ₆ -alkyl.

The meanings of the remaining letters of formula (XIII), including the specific meanings, are each independently as described in the first subset of letters of formulas (IA) and (I) above.

The third subset of letters of formula XIII for the compounds of the present invention is as follows:

The meanings of R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , including the specific meanings, are each independently as described in the second subset of letters of Formula XIII above. .

Ring C is halogen, hydroxy, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ , optionally further substituted with one or more substituents independently selected from the group consisting of -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) And a 7-membered non-aromatic heterocyclic group, wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C _1- Optionally and independently substituted with one or more substituents independently selected from the group consisting of C ₄ alkoxy.

The meanings of the remaining letters of formula (XIII), including the specific meanings, are each independently as described in the first subset of letters of formulas (IA) and (I) above.

The fourth subset of letters of formula XIII for the compounds of the present invention is as follows:

The meanings of R, R ', R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , including the specific meanings, are each independently as described in the third subset of letters of Formula XIII above. .

Ring C is

Independently selected from;

Wherein ring C1 to C5 are each halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), One independently selected from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Optionally and independently substituted with any of the above substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of:

Specifically, rings C1 to C5 are halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C, respectively ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ halo Optionally and independently further substituted with one or more substituents independently selected from the group consisting of alkoxy, C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H and —CO ₂ (C ₁ -C ₄ alkyl).

The meanings of the remaining letters of formula (XIII), including the specific meanings, are each independently as described in the first subset of letters of formulas (IA) and (I) above.

In the fifth subset of letters of formula XIII for the compounds of the invention, the meanings of letters of formula XIII, including the specific meanings, are each independently described in the first subset of letters of formulas IA and I above. As shown.

In another aspect, the invention relates generally to compounds represented by the general formula (XIV) or a pharmaceutically acceptable salt thereof:

Formula XIV

The first subset of letters of formula XIV for the compounds of the present invention is as follows:

Ring D is halogen, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N 4- to 7-membered non-aromatic hetero optionally substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b Cyclic rings; Wherein the alkyl and alkenyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO ( One independently selected from the group consisting of C ₁ -C ₄ alkyl), —CO (C ₁ -C ₄ alkyl), —CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with the above substituents. Specifically, ring D is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), One independently selected from the group consisting of -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) Optionally further substituted with the above substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group. Specifically, ring D is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, Optionally further substituted with one or more substituents independently selected from the group consisting of C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H and —CO ₂ (C ₁ -C ₄ alkyl).

R ⁶ and R ⁷ are each independently —H or —CH _3, or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R ¹³ and R ¹⁴ are each independently —H or —CH ₃ or they together with the carbon atoms to which they are attached form a cyclopropane ring.

R and R 'are each independently -H or C ₁ -C ₆ alkyl.

The meanings of the remaining letters of formula (XIV), including the specific meanings, are each independently as described in the first subset of letters of formulas (IA) and (I).

The second subset of letters of formula XIV for the compounds of the present invention is as follows:

The meanings of the rings D, R, R ', R ⁶ , R ⁷ , R ¹³ and R ¹⁴ , including the specific meanings, are each independently as described in the first subset of letters of the formula XIV.

The variable z is one.

All other letters of formula XIV, including the specific meanings, are each independently as described in the first subset of letters of formulas IA and I above.

The third subset of letters of formula IV for the compounds of the present invention is as follows:

The meanings of z, R, R ', R ⁶ , R ⁷ , R ¹³ and R ¹⁴ , including specific meanings, are each independently as described in the second subset of letters of formula XIV.

Ring D is

Independently selected from the group consisting of;

Wherein ring D1 to D7 are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), respectively ), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H and -CO ₂ (C ₁ -C ₄ alkyl) independently Optionally and independently substituted with one or more substituents selected, wherein said alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C _1- C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ Optionally and independently substituted with one or more substituents independently selected from the group consisting of alkoxy.

Specifically, rings D1 to D7 are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C Optionally and independently further substituted with one or more substituents independently selected from the group consisting of ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H and —CO ₂ (C ₁ -C ₄ alkyl).

Each R ^d is independently —H, C ₁ -C ₆ alkyl, or —C (O) (C ₁ -C ₆ alkyl), wherein the alkyl moieties are each and optionally independently halogen, cyano, hydroxy, Oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl) , —CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy. Specifically, R ^d is each independently -H or a substituent halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ Alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally and independently substituted with one or more groups selected.

The meanings of the remaining letters of formula (XIV), including the specific meanings, are each independently as described in the first subset of letters of formulas (IA) and (I).

In the fourth subset of letters of formula XIV for the compounds of the present invention, the meanings of letters of formula XIV, including the specific meanings, are each independently described in the first subset of letters of formulas IA and I above. As shown.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula I, wherein the letters of the formula are each independently as defined above; here,

이다.R ⁴ is

to be.

Ring E is a C ₄ -C ₈ non-aromatic carbocycle optionally further substituted with one or more J ^A.

Ring F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more J ^El .

Rings G1 and G2 are each independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more J ^A.

Q ² is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO ₂ -,- OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- .

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or iv) an optionally substituted 4-7 membered non-aromatic heterocycle; Optionally together with R and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered non-aromatic heterocycle. The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₇ ratio Optionally substituted with one or more substituents independently selected from the group consisting of aromatic carbocycles and optionally substituted 4-7 membered non-aromatic heterocycles; Wherein R ⁵ indicated by the carbocycle and heterocycle, and R ⁵ represented by the above C ₁ -C ₆ carbocycle, and heterocycle mentioned for the substituent of the alkyl group, respectively, halogen, cyano, hydroxy, oxo , C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O ) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl) and -CO ₂ H independently selected from the group Independently and optionally substituted with one or more substituents, wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy Optionally and independently substituted with one or more substituents independently selected from the group consisting of:

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ Alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl; Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls.

R ²¹ , R ²² , R ²³ and R ²⁴ are each independently —H, halogen, —OH, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ One or more substituents independently selected from the group consisting of -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Optionally substituted C ₁ -C ₆ alkyl.

p and q are each independently 0, 1 or 2.

x is 0, 1 or 2.

r is 1 or 2.

The meanings of the remaining letters of formula (I), including the specific meanings, are each independently as described in any one of the first to fifteen sets of letters of formula (I).

In another embodiment, the compounds represented by formula (I) or pharmaceutically acceptable salts thereof are independently as described above in the preceding sections; Ring F is selected from any one of rings F1 to F6:

Rings F1 to F6 are each optionally and independently substituted;

Each R ^f is independently —H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, cyano C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy, and hydroxy is hydroxy C ₂ -C ₆ alkoxyalkoxy groups independently optionally substituted with one or more substituents and independently represent a substituted C ₁ -C ₆ alkyl from consisting of.

In another embodiment, the compounds represented by formula XIA or XIB or pharmaceutically acceptable salts thereof are as described above;

이고;Group-[C (R ¹³ R ¹⁴ )] _x -ring AQ ² -R ⁵ are independently

ego;

Wherein rings A14 and A28 are each optionally and independently substituted further;

The meanings of the remaining letters of the formulas XIA and XIB are the same as described in any one of the first to eleventh sets of letters of the formulas XIA and XIB, each independently including a specific meaning.

In another embodiment, the compounds represented by formula XIA or XIB, or a pharmaceutically acceptable salt thereof, are independently as described above in the preceding sections; R ⁵ is an optionally substituted C ₁ -C ₆ alkyl group; Optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Or an optionally substituted 4-7 membered non-aromatic heterocycle; Optionally together with R and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered non-aromatic heterocycle. Specifically, R ⁵ is an optionally substituted 4-7 membered non-aromatic heterocycle; Optionally together with R and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered non-aromatic heterocycle.

In another embodiment, such compounds or pharmaceutically acceptable salts are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Ring E is a C ₄ -C ₁₀ non-aromatic carbocycle optionally further substituted with one or more J ^A.

Ring F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more J ^El . In a specific example of ring F,

이 포함된다.

This includes.

이 포함된다. 환 F1 내지 F7은 각각 임의로 그리고 독립적으로 치환된다. 환 F(환 F1 내지 F7 포함)에 대한 대표적인 치환체로는 할로겐, 시아노, 하이드록시, C₁-C₄ 알콕시, 및 치환체인 할로겐, 시아노, 하이드록시 및 -O(C₁-C₄ 알킬)로 이루어진 그룹으로부터 선택된 하나 이상의 치환체로 임의로 치환된 C₁-C₄ 알킬이 포함된다.An additional example is

This includes. Rings F1 to F7 are each optionally and independently substituted. Representative substituents for ring F (including rings F1 to F7) include halogen, cyano, hydroxy, C ₁ -C ₄ alkoxy, and the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl) C ₁ -C ₄ alkyl optionally substituted with one or more substituents selected from the group consisting of:

R ^f is independently —H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C C ₁ -C ₆ alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of _1- C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy.

R ⁹ is, independently, —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ Alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy , C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy or C ₂ -C ₆ alkoxyalkoxy.

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl.

Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls.

s is 0, 1 or 2.

x is 0, 1 or 2.

The remaining letters are each independently as described in any one of the sets of letters for Formulas IA and I above.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula I or IA, wherein

Ring E is a C ₄ -C ₈ non-aromatic carbocycle optionally further substituted with one or more J ^A.

R ⁹ is independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl,- O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl) or —N (C ₁ -C ₄ alkyl) ₂ .

The other characters are each independently as described in the previous section.

In another embodiment, such compounds or pharmaceutically acceptable salts are represented by Formula IA or I, wherein

이다. R ⁴ is

to be.

Rings G1 to G4 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^A.

Ring G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^B.

X is -O-, -S- or -NR ^g- .

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, amino, carboxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _1- C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy or C ₂ -C ₆ alkoxyalkoxy.

R ¹³ and R ¹⁴ are each independently —H, halogen, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _1- C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy to be.

Optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyls.

R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy With C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of: Specifically, R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC Consisting of (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl) and -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group.

R ^g is —H, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy.

q is 0, 1 or 2; x is 0, 1 or 2; r is 1 or 2.

The remaining letters are each independently as described in any set of letters for Formulas IA and I above.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein

이고,R ⁴ is

ego,

Wherein rings G 1 and G 2 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^A.

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ Alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

R ²¹ , R ²² , R ²³ and R ²⁴ are each independently —H, halogen, —OH, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ One or more substituents independently selected from the group consisting of -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy Optionally substituted C ₁ -C ₆ alkyl.

Q ² is, independently, a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO ₂ -,- OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- . Alternatively, Q ² is independently -O-, -CO _2- , -OC (O)-, -C (O) NR-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -CO ₂ SO _2- , -P (O) ₂ O- or-(CR ⁶ R ⁷ ) _p -Y ^1- . In contrast, Q ² is independently —O— or —CO ₂ —.

In some embodiments, rings E and G (including rings G1 to G5) are optionally and independently further substituted with one or more J ^A (for carbocycles) or J ^B (for heterocycles), wherein J ^A and Each J ^B is independently selected from the group consisting of halogen, cyano, oxo, -NCO and Q ¹ -R ⁵ , wherein

Q ¹ is independently a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO ₂ -,- OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- ; Y ¹ is, independently, a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO ₂ -, -OC (O) NR'-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO ₂ -or -NRSO ₂ NR'-.

Alternatively, Q ¹ is independently a bond, -O-, -S-, -NR-, -C (O)-, -CO _2- , -OC (O)-, -C (O) NR-,- C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR- , -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ NR'-, -NRSO ₂ NR'- or-(CR ⁶ R ⁷ ) _p -Y ^1- ; Y ¹ is independently —O—, —CO ₂ —, —OC (O) —, —C (O) NR—, —NRC (O) —, —NRC (O) NR—, —NRCO ₂ — or — OC (O) NR-.

In another embodiment, Q ¹ and Y ¹ are each independently as described above in the preceding paragraphs,

R ⁵ is independently i) -H; ii) a C ₁ -C ₆ -aliphatic group optionally substituted with one or more J ^C1 ; iii) C ₃ -C ₈ non-aromatic carbocycle optionally substituted with one or more J ^C1 ; iv) a phenyl group optionally substituted with one or more J ^C1 ; v) 4- to 8-membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ; Or vi) a 5 or 6 membered heteroaryl ring optionally substituted with one or more J ^D1 ;

J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NHR ^c , -C (O ) R ^b , -C (O) OR ^b , -OC (O) R ^b , -NHC (O) R ^b , -C (O) NHR ^c , -NHC (O) NHR ^c , -NHC (O) OR ^b , -OCONHR ^c , -NHC (O) NHC (O) OR ^b , -N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) R ^b , -C (O) N (CH ₃ ) R ^c , -N (CH ₃ ) C (O) NHR ^c , -N (CH ₃ ) C (O) OR ^b , -OCON (CH ₃ ) R ^c , -C (O) NHCO ₂ R ^b , -C (O) N (CH ₃ ) CO ₂ R ^b , -N (CH ₃ ) C (O) NHC (O) OR ^b , -NHSO ₂ R ^b , -SO ₂ NHR ^b , -SO ₂ N (CH ₃ ) R ^b and —N (CH ₃ ) SO ₂ R ^b .

In some specific embodiments, such compounds are represented by Formula IA or I, wherein

R ¹ is -H.

R ² is —H, —CH ₃ , —CH ₂ OH or —NH ₂ . Specifically, R ² is -H or -CH ₂ OH.

R ³ is —H, —F, —Cl, C _1-4 alkyl or C _1-4 haloalkyl. Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is C ₁ -C ₆ alkyl optionally substituted with —H, or one or more substituents independently selected from the group consisting of the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

Z ³ is -H or C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl).

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; iv) optionally substituted 4-7 membered non-aromatic heterocycle; v) an optionally substituted phenyl group; Or vi) an optionally substituted 5 or 6 membered heteroaryl ring; Optionally, together with R and the nitrogen atom to which it is attached, form an optionally substituted 5-7 membered non-aromatic heterocycle;

The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, -NRCO (C ₁ -C ₄ alkyl ), -CONR (C ₁ -C ₄ alkyl), -NRCO ₂ (C ₁ -C ₄ alkyl), a C ₃ -C ₇ non-aromatic carbocycle optionally substituted with one or more J ^E1 substituents, one or more substituents 4- to 7-membered non-aromatic heterocycle optionally substituted with J ^El ; And one or more substituents independently selected from the group consisting of phenyl optionally substituted with one or more J ^El which is a substituent;

Wherein the carbocycle, heterocycle, phenyl and heteroaryl represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ Alkyl), —C (O) O (C ₁ -C ₄ alkyl) and —CO ₂ H independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cya Furnace, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ Optionally and independently substituted with one or more substituents independently selected from the group consisting of -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

The remaining characters, including R ⁴ , comprising a spiro ring represented by rings E and F or a bridged ring represented by rings G1 to G5, are each independently as described in any one of the preceding four embodiments. same.

In another embodiment, the compounds are represented by Formula IA or I, wherein the meanings of the letters are each independently as described in the preceding embodiments, provided that

Z ² is -H;

Z ³ is -H;

R ⁵ is independently i) -H or ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O ) O (C ₁ -C _{4 alkyl), -CO 2 H, C 3} -C 8 non-aromatic heterocyclic group of the heteroaryl, phenyl and 5-or 6-membered aromatic carbocycle, a 4-to 8-membered non- A C ₁ -C ₆ -alkyl group optionally substituted with one or more substituents independently selected from the group consisting of;

Wherein the alkyl groups mentioned in the substituents of the C ₁ -C ₆ -alkyl group represented by R ⁵ are each halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C ₄ alkyl) , -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl ) And optionally one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy;

Wherein the carbocycle, phenyl, heterocycle and heteroaryl mentioned in the substituents of the C ₁ -C ₆ -alkyl group represented by R ⁵ are each halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), Independently and optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

In another embodiment, Rings E and G1 through G5 are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) optionally substituted with one or more substituents selected from the group consisting of (C ₁ -C ₆ alkyl) and -CO ₂ R ^b; Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _1- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy Optionally and independently. Specifically, rings E and G1 to G5 are each independently halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ ,- OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, and a halogen which is a substituent, Optionally substituted with one or more substituents selected from the group consisting of C ₁ -C ₄ alkyl optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Ring A is a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ⁸ optionally form a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ⁹ optionally form a 5-10 membered non-aromatic bridged carbocycle or heterocycle, or Rings A and R ¹¹ optionally form a 5-10 membered non-aromatic bridged carbocycle or Forming a heterocycle, wherein the carbocycles are each independently optionally substituted with one or more J ^A , and the carbocycles are each independently and optionally substituted with one or more J ^B.

R ¹ is -H.

R ² is —H, —CH ₃ , —CH ₂ OH or —NH ₂ . Specifically, R ² is -H or -CH ₂ OH.

R ³ is —H, —F, —Cl, C _1-4 alkyl (eg —CH ₃ or —C ₂ H ₅ ) or C _1-4 haloalkyl (eg —CF ₃ ). Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is C ₁ -C ₆ alkyl optionally substituted with —H, or one or more substituents independently selected from the group consisting of the substituents halogen, cyano, hydroxy and —O (C ₁ -C ₄ alkyl).

Z ³ is -H or C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of substituents halogen, cyano, hydroxy and -O (C ₁ -C ₄ alkyl).

Q ² is independently -O-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O)-,- NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or-(CR ⁶ R ⁷ ) _p -Y ^1- .

Y ¹ is -O-, -CO _2- , -OC (O)-, -C (O) NR'-, -C (O) NRC (O) O-, -NRC (O)-, -NRC ( O) NR'-, -NRCO _2- , -OC (O) NR'-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O -Or -CO ₂ SO _2- .

R ⁵ is i) -H; ii) an optionally substituted C ₁ -C ₆ alkyl group; iii) optionally substituted C ₃ -C ₇ non-aromatic carbocycles; iv) optionally substituted 4-7 membered non-aromatic heterocycle; v) an optionally substituted phenyl group; Or vi) an optionally substituted 5 or 6 membered heteroaryl ring; Optionally, together with R and the nitrogen atom to which it is attached, form an optionally substituted 5-7 membered non-aromatic heterocycle;

The alkyl group represented by R ⁵ is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, -NRCO (C ₁ -C ₄ alkyl ), -CONR (C ₁ -C ₄ alkyl), -NRCO ₂ (C ₁ -C ₄ alkyl), a C ₃ -C ₇ non-aromatic carbocycle optionally substituted with one or more J ^E1 substituents, one or more substituents 4- to 7-membered non-aromatic heterocycle optionally substituted with J ^El ; And one or more substituents independently selected from the group consisting of phenyl optionally substituted with one or more J ^El which is a substituent;

Wherein the carbocycle, heterocycle, phenyl and heteroaryl represented by R ⁵ are halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ Alkyl), —C (O) O (C ₁ -C ₄ alkyl) and —CO ₂ H independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cya Furnace, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ Optionally and independently substituted with one or more substituents independently selected from the group consisting of -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy.

R ⁸ and R ⁹ are each independently —H, halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ Alkoxyalkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ .

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently C, optionally substituted with one or more substituents independently selected from the group consisting of -H, halogen, or substituents halogen, hydroxy and C ₁ -C ₆ alkoxy. _1- C ₆ alkyl.

J ^A and J ^B are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) and -CO ₂ R ^b ; Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _1- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy Optionally and independently.

n is 0 or 1;

x is 0 or 1.

The remaining letters are each independently as described in any set of letters for Formulas IA and I above.

In another embodiment, such compounds or pharmaceutically acceptable salts are represented by Formula IA or I, wherein

이다.R ⁴ is

to be.

Rings G1 to G4 are each independently, a 5- to 10-membered further substituted with optionally substituted with one or more J ^A non-aromatic bridging a carbocycle, the ring G5 is a 5- substituted further optionally substituted with one or more J ^B To 10 membered non-aromatic bridged heterocycles.

X is -O-, -S- or -NR ^g- .

R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, cyano, hydroxy, C ₁ -C ₆ Alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) ( Independently from the group consisting of C ₁ -C ₆ alkyl), —NHC (O) (C ₁ -C ₆ alkyl), and —N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected.

R ^g is —H, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy and C ₂ -C ₆ alkoxyalkoxy.

q is 0, 1 or 2.

r is 1 or 2.

The remaining characters are each independently as described above in the previous section.

In another embodiment, the compounds or pharmaceutically acceptable salts thereof are represented by Formula IA or I, wherein the letters are each independently as described in the preceding sections, except for those described below:

R ¹ is -H.

R ² is -H.

R ³ is —H, —F, —Cl, C _1-4 alkyl or C _1-4 haloalkyl. Alternatively, R ³ is -H, -F or -Cl.

Z ¹ is -H, -F or -Cl.

Z ² is -H.

Z ³ is -H.

X is -O-.

R ⁵ is -H, optionally substituted C ₁ -C ₆ alkyl or optionally substituted phenyl.

Each R ⁸ is independently —H, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl or —O ( C ₁ -C ₄ alkyl).

R ⁹ , R ¹³ and R ¹⁴ are each independently —H or C ₁ -C ₄ alkyl.

R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently —H, halogen, —OH, C ₁ -C ₆ alkoxy, or a substituent halogen, hydroxy, C ₁ -C ₆ alkyl and — O a (C _1- C ₆ alkyl) group optionally substituted by C ₁ -C ₆ with one or more substituents independently selected from consisting of alkyl. Specifically, R ²¹ , R ²² , R ²³ , R ^24, and R ²⁵ are each independently —H, C _1-6 alkyl, or C _1-6 haloalkyl.

Rings G1 to G5 are each halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ Alkyl) and one or more substituents independently and optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy and C ₁ -C ₄ alkoxy and optionally substituted by one or more substituents selected from the group consisting of C ₁ -C ₄ alkyl. .

In another embodiment, the compounds are of Formulas I-VI (hereafter reference to Formulas I-VI include Formulas I, IA, II, III, IV, V and VI) and Formulas XIA-XIV (hereafter Reference to XIA to XIV is represented by any one of the formulas XIA, XIB, XIIA, XIIB, XIII and XIV), wherein the meanings of these letters are independently in any embodiment for the compounds of the present invention. As above, provided that R ³ is C _1-6 alkyl, eg methyl or ethyl.

In another embodiment, the compounds are represented by one of Formulas I-VI and XIA-XIV, wherein the meanings of these letters are independently as described above in any of the embodiments for the compounds of the present invention, X is 0.

In another embodiment, the compounds are represented by any one of Formulas I, IA, II, VI, XIA and XIB, wherein the meanings of these letters are independently as described above in any of the embodiments for the compounds of the present invention. Provided that ring A is bridged.

In another embodiment, the compounds are represented by any one of Formulas I, IA, II, VI, XIA and XIB, wherein the meanings of their letters are independently as described above in any of the embodiments for the compounds of the present invention. Provided that Q ² is independently -C (= NR)-, -C (= NR) NR-, -NRC (= NR) NR-, -CO _2- , -OC (O)-, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) ( OR) O—, —OP (O) (OR ^a ) O—, —P (O) ₂ O—, —CO ₂ SO ₂ — or — (CR ⁶ R ⁷ ) _p -Y ^1- ; Alternatively, Q ² is independently -CO _2- , -OC (O)-, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O- , -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR-, -S (O)-, -SO _2- , -N (R) SO _2- , -SO ₂ N (R)-, -NRSO ₂ NR-, -P (O) (OR) O-, -OP (O) (OR ^a ) O-, -P (O) ₂ O-, -CO ₂ SO ₂ -or-(CR ⁶ R ⁷ ) _p -Y ^1- .

In another embodiment, the compounds are represented by one of Formulas I-VI and XIA-XIV, wherein the meanings of these letters are independently as described above in any of the embodiments for the compounds of the present invention, Provided that when Q ² is -O- or -NR-, ring A is further substituted with J ^A instead of -H; Provided that when Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₈ non-aromatic carbocycles; Optionally substituted 6-10 membered carbocyclic aryl groups; Optionally substituted 4-8 membered non-aromatic heterocycles; Or an optionally substituted 5-10 membered heteroaryl group. In certain embodiments, when Q ² is -O- or -NR-, ring A is further substituted with J ^A instead of -H at the same position relative to -Q ² R ⁵ .

In another embodiment, the invention relates to any one of the compounds shown in FIGS. 3A-5C or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to any one of the compounds shown in FIGS. 6A-6V or pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to any one of the compounds shown in FIGS. 7A-7H, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to any one of the compounds shown in FIGS. 8A and 8B, or a pharmaceutically acceptable salt thereof.

In some embodiments, the letters of Formulas I-VI and XIA-XIV are each independently as shown in the compounds of FIGS. 3A-8B.

The compounds of the invention as described above, each independently in the methods of the invention, may be useful as inhibitors of influenza virus replication in biological samples or patients. These compounds may also be useful for reducing the amount (virus titer) of influenza virus in a biological sample or patient. They may also be useful for the treatment or prophylactic treatment of infections caused by influenza virus in biological samples or patients.

의 화합물을 화학식 B

의 화합물과 반응시켜 화학식 XX로 표시되는 화합물을 형성하는 단계를 포함한다.The invention also provides a process for the preparation of the compounds of the invention. In one embodiment, the method relates to the preparation of compounds represented by formula (IA) or a pharmaceutically acceptable salt thereof. The method is represented by the following formula (A):

Compound of Formula B

Reacting with a compound of to form a compound represented by Formula (XX).

Scheme A

The letters of the compounds of formulas (IA) and (XX) and of formulas (A) and (B) are independently as defined in any one of the aforementioned embodiments. Ts is chubby. The reaction between the compound of formula A and the compound of formula B may be carried out by any suitable reaction conditions known in the art, for example chloro-pyridine dioxaboolalan in WO 2005/095400 and WO 2007/084557. Reaction conditions for coupling with midine can be used. For example, the reaction between the compound of formula A and the compound of formula B can be carried out in the presence of Pd (PPh ₃ ) ₄ . Specific illustrative conditions are given in the following examples (e.g., Schemes 5A, 6A, 7, 11, 14, 16, 31, 32, 33, 40, 44, 49, 51, 52, 58, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 76).

In another embodiment, the method includes reacting a compound of Formula C1 or C2 with NH ₂ R ⁴ to form a compound of Formula XX, as shown in Scheme B below.

Scheme B

The letters of the compounds of formulas IA and XX, the compounds of formulas C1 and C2, and R ⁴ of NH ₂ R ⁴ are independently as defined in any of the above-mentioned embodiments. Ts is chubby. The reaction of NH ₂ R ⁴ with a compound of Formula C1 or C2 may be carried out with any suitable reaction conditions known in the art, for example, with the sulfinyl group in amines in WO 2005/095400 and WO 2007/084557. Reaction conditions for coupling may be used. Specific illustrative conditions are given in the following examples (e.g., Schemes 13, 15, 19, 20, 23, 30, 39, 41, 42, 44, 45, 50, 53, 54, 65, 72, 73, 74 and 77). It is described in

The methods described above with reference to Schemes A and B further optionally and independently comprise deprotecting the Ts group of the compound of formula XX to form a compound of formula IA. Any suitable condition for deprotection of the Ts group known in the art can be used in the present invention. Specific illustrative conditions are described in the Examples below. De-tosylation can produce compounds of formula (IA) in which R ¹ is -H. If desired, the R ¹ position can be alkylated by any suitable method known in the art to form compounds of formula (IA) wherein R ¹ is C _1-6 alkyl.

Compounds of formula A, B, C1 and C2 and NH ₂ R ⁴ may be prepared by any suitable method known in the art. Specific exemplary synthetic methods are described in the Examples below. For example, a compound of Formula C1 can be prepared as described in Scheme C: A compound of Formula D can be reacted with a compound of Formula E in the presence of, for example, Pd (PPh ₃ ) ₄ to produce a compound of Formula F. Can be. The compound of formula F can then be oxidized under suitable conditions, for example by treating with meta-chloroperbenzoic acid, to form the compound of formula C (eg, the detailed experimental details described in the Examples for Scheme 44). See).

Scheme C

Definition and general terms

For the purposes of the present invention, chemical elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition). In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, Smith, M.B. And March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as generally described below or illustrated by certain classes, subclasses, and species of the present invention. It will be understood that the phrase "optionally substituted" can be used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted" preceded by or without the term "optionally" means that one or more hydrogen radicals in a given structure are replaced by radicals of a particular substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of that group. Where one or more positions in a given structure may be substituted with one or more substituents selected from specific groups, the substituents may be the same or different at each position. Where the term "optionally substituted" precedes the list, the term applies to all subsequent substitutable groups in the list. When a substituent radical or structure is not identified or defined as "optionally substituted", the substituent radical or structure is not substituted. For example, when X is optionally substituted C _1-3 alkyl or phenyl, X may be either optionally substituted C _1-3 alkyl or optionally substituted phenyl. Likewise, where the term "optionally substituted" follows the list, the term applies to all of the substitutable groups in the preceding list, unless stated otherwise. For example, wherein X is C _1-3 alkyl or phenyl wherein X is optionally and independently substituted with if that by J ^X, can be a C _1-3 alkyl and phenyl is optionally substituted by J ^X both. As will be apparent to those skilled in the art, groups such as H, halogen, NO ₂ , CN, NH ₂ , OH or OCF ₃ are not substitutable groups.

The term "less than" as used herein refers to any integer equal to or less than zero or a number preceding the term. For example, "3 or less" means any one of 0, 1, 2, and 3. As described herein, the specified number range of atoms includes any integer within that range. For example, a group having 1 to 4 atoms can have 1, 2, 3 or 4 atoms.

The choice of substituents and combinations of substituents contemplated by the present invention are those which lead to the formation of stable or chemically feasible compounds. As used herein, the term “stable” means that the compounds are substantially unchanged in their preparation, detection and in particular their recovery, purification, and conditions of use for one or more purposes described herein. In some embodiments, a stable compound or chemically feasible compound is a compound that does not substantially change when maintained at temperatures below 40 ° C. for at least one week in the absence of moisture or other chemical reaction conditions. Only the selection and combination of substituents leading to stable structures are considered. Such selections and combinations will be apparent to those skilled in the art and may be determined without unnecessary experimentation.

As used herein, the term "aliphatic" or "aliphatic group" refers to a straight (ie unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units but is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In another embodiment, aliphatic groups contain 1-6 aliphatic carbon atoms and in another embodiment, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups can be linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, secondary-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene.

As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon. As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon comprising one or more double bonds. As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon comprising one or more triple bonds. As used herein, "alkyl", "alkenyl" or "alkynyl" may each be optionally substituted as described below. In some embodiments, “alkyl” is C ₁ -C ₆ alkyl or C ₁ -C ₄ alkyl. In some embodiments, “alkenyl” is C ₂ -C ₆ alkenyl or C ₂ -C ₄ alkenyl. In some embodiments, “alkynyl” is C ₂ -C ₆ alkynyl or C ₂ -C ₄ alkynyl.

The term "cycloaliphatic" (or "carbocycle" or "carbocyclyl" or "carbocyclic") is a ratio that may contain saturated or one or more unsaturated units, having 3 to 14 ring carbon atoms. -Means a ring system containing only aromatic carbon. In some embodiments, the number of carbon atoms is 3 to 10. In another embodiment, the number of carbon atoms is 4-7. In another embodiment, the number of carbon atoms is five or six. The term includes monocyclic, bicyclic or polycyclic, fused, spiro or bridged carbocyclic ring systems. The term also refers to the fact that the carbocyclic ring may be “fused” to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof and where a radical or point of attachment is present on the carbocyclic ring. Also included are polycyclic ring systems. A "fused" bicyclic ring system includes two rings that share two adjacent ring atoms. Bridged bicyclic groups include two rings that share three or four neighboring ring atoms. Spiro bicyclic ring systems share one ring atom. Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl and cyclobutyl.

As used herein, the term “heterocycle” (or “heterocyclyl” or “heterocyclic” or “non-aromatic heterocycle”) has 3 to 14 ring atoms, wherein one or more ring carbons is Replaced by a heteroatom such as N, S or O, each ring in the system means a non-aromatic ring system which may contain 3 to 7 members, which may be saturated or may contain one or more unsaturated units . In some embodiments, the non-aromatic heterocyclic ring contains up to three heteroatoms selected from N, S, and O in the ring. In other embodiments, the non-aromatic heterocyclic ring comprises up to two heteroatoms selected from N, S and O in the ring system. In another embodiment, the non-aromatic heterocyclic ring comprises up to two heteroatoms selected from N and O in the ring system. The term includes monocyclic, bicyclic or polycyclic, fused, spiro or bridged heterocyclic ring systems. The term also refers to a poly in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof and where a radical or point of attachment is present on the heterocyclic ring. Also included are cyclic ring systems. Examples of heterocycles include, but are not limited to, piperidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazpanyl, azocanyl, diazoca Neil, triazokaniyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazokanyl, oxazpanilyl, thiazpanyl, thiazocanyl, benzimidazolonil, tetrahydrofuranyl , Tetrahydrothiophenyl, morpholino, for example, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-py Lolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl , 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-pipe Ridinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imi Dazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzoditianyl, 3- (1-alkyl) -benzimidazole-2- Onyl and 1,3-dihydroimidazole-2-onyl.

The term "aryl" (or "aryl ring" or "aryl group"), used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy", "aryloxyalkyl" or "heteroaryl". Denotes both carbocyclic or heterocyclic aromatic ring systems. The term "aryl" can be used interchangeably with the term "aryl ring" or "aryl group".

A “carbocyclic aromatic ring” group has only carbon ring atoms (typically 6 to 14) and is a fused polycyclic aromatic in which a monocyclic aromatic ring such as phenyl and two or more carbocyclic aromatic rings are fused to each other Ring system. Examples include 1-naphthyl, 2-naphthyl, 1-anthrasyl and 2-anthrasyl. Within the scope of the term “carbocyclic aromatic ring” or “carbocyclic aromatic” as used herein, an aromatic ring is a group “fused” to one or more non-aromatic rings (carbocyclic or heterocyclic), eg For example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl or tetrahydronaphthyl are also included, wherein a radical or point of attachment is present on the aromatic ring.

The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group”, “used alone or as part of a larger moiety, such as in“ heteroaralkyl ”or“ heteroarylalkoxy ” Aromatic heterocycle "or" heteroaromatic group "means a heteroaromatic ring group having from 5 to 14 members, and a monocyclic heteroaromatic ring and a polycyclic in which the monocyclic aromatic ring is fused to one or more other aromatic rings And click aromatic rings. Heteroaryl groups have one or more ring heteroatoms. Within the scope of the term “heteroaryl” as used herein, also includes groups in which an aromatic ring is “fused” to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the radical or point of attachment is said aromatic Present in the ring. For example, as used herein, a bicyclic 6,5 heteroaromatic ring is a ring in which a 6-membered heteroaromatic ring is fused to a second 5-membered ring, wherein the radical or point of attachment is on the 6-membered ring exist. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadizolyl, thiazolyl, Isothiazolyl or thiadiazolyl (e.g. 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxa Zolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl , 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3 -Pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl , Benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazole , Benzimidazolyl, isoquinolinyl, indolyl, isoindoleyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, furi Neil, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g. 1-isoqui Nolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

As used herein, a "cyclo", "cyclic", "cyclic group" or "cyclic moiety" refers to mono-, bi- and including cycloaliphatic, heterocycloaliphatic, carbocyclic aryl or heteroaryl. Tri-cyclic ring systems, each of which has been defined above.

As used herein, “bicyclic ring system” includes structures of 8 to 12 members (eg, 9, 10 or 11 members) that form two rings, wherein the two rings are Have at least one atom (eg two atoms) in common. Bicyclic ring systems include bicycloaliphatic (eg bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic carbocyclic aryl and bicyclic heteroaryl.

As used herein, “bridged bicyclic ring system” means a bicyclic heterocycloaliphatic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1 ] Nonyl, bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl And 2,6-dioxa-tricyclo [3.3.1.03,7] nonyl. Bridged bicyclic ring systems include alkyl (carboxyalkyl, hydroxyalkyl and haloalkyl, including, for example, trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl , (Heterocycloalkyl) alkyl, carbocyclic aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl) oxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl , Heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, (carbocyclic aryl) carbonyl Amino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonyl No, cyano, optionally substituted by halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfonic epoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or one or more substituents, such as carbamoyl.

As used herein, "bridge" refers to a bond or unbranched chain of atoms or atoms that connects two different parts of a molecule. Two atoms connected via bridged (not necessarily but usually two tertiary carbon atoms) are referred to as "bridgeheads".

As used herein, the term “spiro” refers to a ring system having one atom (usually quaternary carbon) as the only common atom between two rings.

The term "ring atom" is an atom such as C, N, O or S present in a ring of an aromatic group, a cycloalkyl group or a non-aromatic heterocyclic ring.

A "substitutable ring atom" in an aromatic group is a carbon or nitrogen ring atom bonded to a hydrogen atom. Hydrogen may be optionally substituted with a suitable substituent group. Thus, the term "substitutable ring atom" does not include nitrogen or carbon ring atoms shared when two rings are fused. In addition, the "substitutable ring atom" does not include the carbon or nitrogen ring atoms in the case of a structure in which carbon or nitrogen ring atoms are already attached to a residue other than hydrogen.

The term “heteroatom” refers to one or more oxygen, sulfur, nitrogen, phosphorus or silicon (nitrogen, sulfur, phosphorus or silicon in oxidized form; any basic nitrogen in quaternized form; or substitutable nitrogen of a heterocyclic ring, eg For example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl).

As used herein, optionally substituted aralkyl may be substituted in both the alkyl and aryl moieties. Unless otherwise specified, as used herein, optionally substituted aralkyl is optionally substituted in the aryl moiety.

In some embodiments, an aliphatic or heteroaliphatic group or non-aromatic heterocyclic ring can contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group or non-aromatic heterocyclic ring are selected from those listed above, for example those listed in the definition of J ^A , J ^B , J ^C1 , J ^D1 and J ^E1 . . Other suitable substituents include those listed as suitable for the unsaturated carbon of the carbocyclic aryl or heteroaryl group, and further include the following: = O, = S, = NNHR ^* , = NN (R ^* ) ₂ , = NNHC (O) R ^* , = NNHCO ₂ (alkyl), = NNHSO ₂ (alkyl) or = NR ^* , where R ^* are each independently selected from hydrogen or optionally substituted C _1-6 aliphatic. Any substituent on an aliphatic group of R ^* is NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O (C _1-4 aliphatic) , NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic) or halo (C _1-4 aliphatic), wherein the C _1- of R ^* ₄ aliphatic groups are each unsubstituted.

In some embodiments, any substituent on the nitrogen of the non-aromatic heterocyclic ring includes those used above, such as those used in the definition of J ^B , J ^D1 and J ^E1 . Other suitable substituents include -R ⁺ , -N (R ⁺ ) ₂ , -C (O) R ⁺ , -CO ₂ R ⁺ , -C (O) C (O) R ⁺ , -C (O) CH ₂ C (O) R ⁺ , -SO ₂ R ⁺ , -SO ₂ N (R ⁺ ) ₂ , -C (= S) N (R ⁺ ) ₂ , -C (= NH) -N (R ⁺ ) ₂ Or -NR ⁺ SO ₂ R ⁺ ; Wherein R ⁺ is hydrogen, optionally substituted C _1-6 aliphatic, optionally substituted phenyl, optionally substituted -O (Ph), optionally substituted -CH ₂ (Ph), optionally substituted-(CH ₂ ) _1-2 (Ph); Optionally substituted -CH = CH (Ph); Or an unsubstituted 5 or 6 membered heteroaryl or heterocyclic ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, or two independent R ⁺ on the same substituent or on different substituents , Together with the atom (s) to which each R ⁺ group is bonded, forms a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein The heteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. The aliphatic group of R ⁺ or any substituent on the phenyl ring is NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O (C _{1- 4} aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic) or halo (C _1-4 aliphatic), wherein R ⁺ Each C _1-4 aliphatic group is unsubstituted.

In some embodiments, carbocyclic aryl (including aralkyl, aralkoxy, aryloxyalkyl, etc.) or heteroaryl (including heteroaralkyl, heteroarylalkoxy, etc.) groups may contain one or more substituents. Suitable substituents on unsaturated carbon atoms of carbocyclic aryl or heteroaryl groups are selected from those listed above, for example those listed in the definitions of J ^A , J ^B , J ^C1 , J ^D1 and J ^E1 . Other suitable substituents include halogen; -R ⁰ ; -OR ⁰ ; -SR ⁰ ; 1,2-methylenedioxy; 1,2-ethylenedioxy; Phenyl (Ph) optionally substituted with R ^o ; -O (Ph) optionally substituted with R ^o ; -(CH ₂ ) _1-2 (Ph), optionally substituted with R ^o ; -CH = CH (Ph) optionally substituted with R ^o ; -NO ₂ ; -CN; -N (R ^o ) ₂ ; -NR ^o C (O) R ⁰ ; -NR ^o C (S) R ⁰ ; -NR ^o C (O) N (R ⁰ ) ₂ ; -NR ^o C (S) N (R ⁰ ) ₂ ; -NR ^o CO ₂ R ⁰ ; -NR ^o NR ^o C (O) R ⁰ ; -NR ^o NR ^o C (O) N (R ⁰ ) ₂ ; -NR ^o NR ^o CO ₂ R ⁰ ; -C (O) C (O) R ⁰ ; -C (O) CH ₂ C (O) R ⁰ ; -CO ₂ R ⁰ ; -C (O) R ⁰ ; -C (S) R ⁰ ; -C (O) N (R ⁰ ) ₂ ; -C (S) N (R ⁰ ) ₂ ; -OC (O) N (R ⁰ ) ₂ ; -OC (O) R ⁰ ; -C (O) N (OR ⁰ ) R ⁰ ; -C (NOR ⁰ ) R ⁰ ; -S (O) ₂ R ⁰ ; -S (O) ₃ R ⁰ ; -SO ₂ N (R ⁰ ) ₂ ; -S (O) R ⁰ ; -NR ⁰ SO ₂ N (R ⁰ ) ₂ ; -NR ⁰ SO ₂ R ⁰ ; -N (OR ⁰ ) R ⁰ ; -C (= NH) -N (R ⁰ ) ₂ ; Or-(CH ₂ ) _0-2 NHC (O) R ⁰ ; Wherein each R ⁰ is independently from hydrogen, optionally substituted C _1-6 aliphatic, unsubstituted 5- or 6-membered heteroaryl or heterocyclic ring, phenyl, —O (Ph) or —CH ₂ (Ph) Or two independent R ⁰ on the same or different substituents, together with the atom (s) to which each R ⁰ group is bonded, is a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl Ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Any substituent on the aliphatic group of R ⁰ is NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O (C _1-4 aliphatic) , NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (haloC _1-4 aliphatic), or haloC _1-4 aliphatic, CHO, N (CO) (C _1-4 aliphatic ) Or C (O) N (C _1-4 aliphatic) wherein the C _1-4 aliphatic groups of R ⁰ are each unsubstituted.

A non-aromatic nitrogen containing heterocyclic ring that is substituted on ring nitrogen and attached to the rest of the molecule at the ring carbon atom is said to be N substituted. For example, an N alkyl piperidinyl group is attached to the remainder of the molecule at the 2, 3 or 4 position of the piperidinyl ring and substituted with an alkyl group under ring nitrogen. Non-aromatic nitrogen containing heterocyclic rings, such as pyrazinyl, substituted on ring nitrogen and attached to the remainder of the molecule at the second ring nitrogen atom, are referred to as N 'substituted -N-heterocycles. For example, the N 'acyl N-pyrazinyl group is attached to the rest of the molecule at one ring nitrogen atom and substituted with an acyl group at the second ring nitrogen atom.

As used herein, the term “unsaturated” means that the residue has one or more unsaturated units.

에서, 이들 2개의 R⁰이 이들이 결합되어 있는 산소 원자들과 함께 형성한 융합된 6원 산소 함유 환

이 포함되지만, 이에 제한되지는 않는다. 2개의 독립적인 R⁰(또는 R⁺, 또는 본원 명세서에서 유사하게 정의된 임의의 다른 문자)은 각각의 문자가 결합된 원자(들)와 함께 기타의 각종 환을 형성할 수 있으며, 상술된 예들에 제한되지 않는다는 것을 이해할 것이다.As described above, in some embodiments, two independent R ⁰ (or R ⁺ , or any other letter similarly defined herein), together with the atom (s) to which each letter is bound, is 5 One to eight membered heterocyclyl, carbocyclic aryl or heteroaryl rings or three to eight membered cycloalkyl rings can be formed. Examples of rings in which two independent R ^0s (or R ⁺ , or any other letter similarly defined herein) are formed with the atom (s) to which each letter is bonded, include: (a) two independent R ⁰ (or R ⁺ , or any other character similarly defined herein) is bonded to the same atom and formed with the atom, for example, two R in N (R ⁰ ) ₂ A piperidin-1-yl, piperazin-1-yl or morpholin-4-yl group wherein ⁰ is formed with a nitrogen atom; And (b) two independent R ⁰ (or R ⁺ , or any other letter similarly defined herein) bonded to different atoms and formed together with both of those atoms, eg, phenyl The group is replaced by two OR ⁰

In which these two R ⁰ are formed together with the oxygen atoms to which they are bonded

Includes, but is not limited to. Two independent R ⁰ (or R ⁺ , or any other letter similarly defined herein) together with the atom (s) to which each letter is bound may form other various rings, as described above. Will be understood.

In some embodiments, the alkyl or aliphatic chain may optionally be interrupted by other atoms or groups. This means that the methylene units of an alkyl or aliphatic chain are optionally replaced with said other atoms or groups. Examples of such atoms or groups include, but are not limited to, those listed in the definitions of Q ¹ , Y ¹ , Q ² and Q ³ . Further examples are -NR-, -O-, -S-, -CO _2- , -OC (O)-, -C (O) CO-, -C (O)-, -C (O) NR- , -C (= N-CN) -, -NRCO-, -NRC (O) O-, -SO 2 NR-, -NRSO 2 -, -NRC (O) NR-, -OC (O) NR-, —NRSO ₂ NR—, —SO—, or —SO ₂ —, wherein R is as defined above.

As used herein, an “amino” group is a group wherein R ^X and R ^Y are each, independently, —H, C ₁ -C ₆ aliphatic, C _3-7 non-aromatic carbocycle, 5- or 6-membered carbosai Or -NR ^X R ^Y , which is a click aryl or heteroaryl or a 4-7 membered non-aromatic heterocycle, each of which is independently defined herein and optionally substituted. Suitable substituents for the carbocycle, carbocyclic aryl, heteroaryl and heterocycle are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -NHC (O) O (C ₁ -C ₆ alkyl), -C (O) NH ( C ₁ -C ₆ alkyl) and -C (O) N (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO Optionally and independently substituted with one or more substituents selected from the group consisting of ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy. Suitable substituents for the C ₁ -C ₆ aliphatic (including C ₁ -C ₆ alkyl) include halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N ( C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) OH, -C (O) O (C ₁ -C ₆ alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -NHC (O) O (C ₁ -C ₆ alkyl), -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered non-aromatic heterocycle and C ₃ -C ₇ carbocycle, Wherein the alkyl groups are halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C _1- C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and one or more substituents selected from the group consisting of C ₁ -C ₄ alkoxy and Independently substituted, the phenyl, heteroaryl, heterocycle and carbocycle are each optionally and independently To, and is substituted with the R ^X and carbocycle, carbocyclic aryl, heterocyclic aryl, and one or more of the substituents described for the heterocycle represented by R ^Y. In some embodiments, R ^X and R ^Y are each, independently, —H, an optionally substituted C _1-6 aliphatic group, or an optionally substituted C _3-8 non-aromatic carbocycle. In some embodiments, R ^X and R ^Y are each independently —H or an optionally substituted C _1-6 aliphatic group. In some embodiments, R ^X and R ^Y are each, independently, -H, or substituents halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C C _1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of ₄ alkoxy. Examples of amino groups include -NH ₂ , aliphatic amino, alkylamino, dialkylamino or arylamino. As used herein, an “aliphatic amino” group is a C _1-6 aliphatic group where R ^X is optionally substituted as described above; R ^Y is -H, or -NR ^X R ^Y , which is an optionally substituted C _1-6 aliphatic group as described above. As used herein, an "alkylamino" group refers to -NHR ^{X wherein} R ^X is an optionally substituted C _1-6 alkyl group as described above. As used herein, a "dialkylamino" group refers to -NR ^X R ^Y , wherein R ^X and R ^Y are each independently an optionally substituted C _1-6 alkyl group as described above. As used herein, an "arylamino" group is a group wherein R ^X is 5- or 6-membered carbocyclic aryl or heteroaryl, and R ^Y is -H or 5- or 6-membered carbocyclic aryl or heteroaryl. means (here, the carbocyclic aryl, and heteroaryl groups is optionally substituted as described above, each independently) is -NR ^X R ^Y. If the term "amino" is not a terminal group (eg alkylcarbonylamino), it is represented by -NR ^X- . R ^X has the same meaning as defined above. In one embodiment, the amino group is -NH ₂ or aliphatic amino. In another embodiment, the amino group is —NH ₂ , alkylamino or dialkylamino. In another embodiment, the amino group is -NH ₂ or arylamino. In another embodiment, the amino group is -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each halogen, cyano, hydroxy , Oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl ), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents selected from the group consisting of.

As used herein, "amido" includes both "aminocarbonyl" and "carbonylamino". These terms, when used alone or in combination with another group, are N (R ^X R ^Y ) -C (O)-or R ^Y C (O) -N (R ^X )-and internal when used at the end; when used in the ^{-C (O) -N (R X} ) - or ^{-N (R X) -C (O} ) - means the amido group, such as, where R ^X and R ^Y are as defined above . Examples of amido groups include alkylamido (e.g., alkylcarbonylamino or alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) amido, (heteroaralkyl) amido, (heteroaryl) amido , (Heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido or cycloalkylamido. In some embodiments, the amido group is selected from -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -C (O) NH ₂ , —C (O) NH (C ₁ -C ₆ alkyl) or —C (O) NH (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl is each optionally and independently halogen, cyano, hydroxy Roxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ Alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy. In some embodiments, the amido group is selected from -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -C (O) NH ₂ , —C (O) NH (C ₁ -C ₆ alkyl) or —C (O) NH (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each halogen, cyano, hydroxy, Oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl) , -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy are optionally and independently substituted with one or more substituents selected from the group consisting of.

As used herein, a "urea" group refers to the structure -NR ^X -CO-NR ^Y R ^Z , and a "thiourea" group, when used at the end, represents a structure -NR ^X -CS-NR ^Y R ^Z , and When used internally, it means the structure -NR ^X -CO-NR ^Y -or -NR ^X -CS-NR ^Y- , wherein R ^X , R ^Y and R ^Z are each independently as defined above.

As used herein, an "acyl" group refers to a formyl group or R ^X -C (O)-(eg, -alkyl-C (O)-, also referred to as "alkylcarbonyl"), where R ^X and "alkyl" have been defined above. Examples of acyl groups are acetyl and pivaloyl.

As used herein, a "carboxy" group, when used as a terminal group, is -COOH, -COOR ^X , -OC (O) H, -OC (O) R ^X ; Or -OC (O)-or -C (O) O- when used as an internal group, wherein R ^x is as defined above.

The term "hydroxyl" or "hydroxy" or "alcohol residue" means -OH.

As used herein, the term "alkoxycarbonyl" included in the term carboxy means a group such as (alkyl-O) -C (O)-when used alone or in combination with another group.

As used herein, "carbonyl" means -C (O)-.

As used herein, "oxo" means = O.

As used herein, the term “alkoxy” or “alkylthio” is attached to the molecule via an oxygen (“alkoxy”, such as —O-alkyl) or sulfur (“alkylthio”, such as —S-alkyl) atom. , An alkyl group as defined above.

As used herein, the terms "halogen", "halo" and "hal" mean F, Cl, Br or I.

As used herein, the term "cyano" or "nitrile" means -CN or -C≡N.

The terms "alkoxyalkyl", "alkoxyalkenyl", "alkoxyaliphatic" and "alkoxyalkoxy" mean in each case alkyl, alkenyl, aliphatic or alkoxy substituted with one or more alkoxy groups.

The terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" mean in each case alkyl, alkenyl, aliphatic or alkoxy substituted with one or more halogen atoms. This term includes perfluorinated alkyl groups such as -CF ₃ and -CF ₂ CF ₃ .

The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic" and "cyanoalkoxy" mean in each case alkyl, alkenyl, aliphatic or alkoxy substituted with one or more cyano groups. In some embodiments, cyanoalkyl is (NC) -alkyl-.

The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic" and "aminoalkoxy" mean in each case alkyl, alkenyl, aliphatic or alkoxy substituted with one or more amino groups, wherein the amino group is As defined. In some embodiments, the aminoaliphatic is a C1-C6 aliphatic group substituted with one or more -NH ₂ groups. In some embodiments, aminoalkyl refers to the structure (R ^X R ^Y ) N-alkyl-, wherein R ^X and R ^Y are each independently as defined above. In some specific embodiments, aminoalkyl is C1-C6 alkyl substituted with one or more -NH ₂ groups. In some specific embodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one or more -NH ₂ groups. In some embodiments, aminoalkoxy is —O (C 1 -C 6 alkyl), wherein said alkyl group is substituted with one or more —NH ₂ groups.

The terms "hydroxyalkyl", "hydroxyaliphatic" and "hydroxyalkoxy" mean in each case alkyl, aliphatic or alkoxy substituted with one or more -OH groups.

The terms "alkoxyalkyl", "alkoxyaliphatic" and "alkoxyalkoxy" mean in each case alkyl, aliphatic or alkoxy substituted with one or more alkoxy groups. For example, "alkoxyalkyl" means an alkyl group, such as (alkyl-O) -alkyl-, wherein alkyl is as defined above.

The term "carboxyalkyl" refers to alkyl substituted with one or more carboxy groups, where alkyl and carboxy are as defined above.

In some embodiments, amino groups (eg, R ⁶ , R ⁷ , J ^E1 , R, R ', R ", R ^* , R ^a , mentioned in the description of the letters of Formulas I-VI and XIA-XIV, R ^b and R ^c ) are each independently -NH ₂ , -NH (C ₁ -C ₆ alkyl), -NH (C ₃ -C ₆ carbocycle), -N (C ₁ -C ₆ alkyl) ₂ or- N (C ₁ -C ₆ alkyl) (C ₃ -C ₆ carbocycle), wherein the alkyl and carbocycle groups are each optionally and independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH ( C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ Substituted with one or more substituents independently selected from the group consisting of (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy; the carboxy group mentioned in the description of the letters of formulas I to VI and XIA to XIV ( Example: R ⁶ , R ⁷ , J ^E1 , R, R ', R ", R ^* , R ^a , R ^b and R ^c ) are each independently -C (O) O (C ₁ -C ₆ alkyl), -OC (O) (C ₁ -C ₆ alkyl), -C (O) O (C ₃ -C ₆ carbocycle), -OC (O) (C ₃ -C ₆ carbocycle) or -CO ₂ H, wherein the alkyl and carbocycle groups Is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), Optionally substituted with one or more substituents independently selected from the group consisting of -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy; Amido groups (e.g., R ⁶ , R ⁷ , J ^E1 , R, R ', R ", R ^* , R ^a , R ^b and mentioned in the description of the letters of formulas I to VI and XIA to XIV R ^c ) are each independently —NHC (O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -NHC (O) (C ₃ -C ₆ carbocycle), -N (C ₁ -C ₆ alkyl) C (O) (C ₃ -C ₆ carbocycle), -C (O) NH (C ₃ -C ₆ carbocycle), -C (O) N (C ₁ -C ₆ alkyl) (C ₃ -C ₆ Carbocycle) or -C (O) NH ₂ , wherein the alkyl and carbocycle groups are each and optionally independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl) , -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl And one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy; in the descriptions of the letters of formulas I to VI and XIA to XIV Aminoalkyl groups (e.g., R ⁸ , R ⁹ and R ") mentioned each independently represent -NH ₂ , -NH (C ₁ -C ₄ alkyl) and -N (C ₁ -C ₄ alkyl) ₂ A C1-C6 alkyl group substituted with one or more amino groups independently selected from the group consisting of: Aminoalkoxy groups mentioned in the description of the letters of formulas I to VI and XIA to XIV (e.g., R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R, R 'and R ") are each independently selected from the group wherein the alkyl group is -NH ₂ , -NH (C ₁ -C ₄ alkyl) and -N (C ₁ -C ₄ alkyl) ₂ -O (C1-C6 alkyl) group substituted with one or more amino groups.

In some embodiments, amino groups (eg, R ⁶ , R ⁷ , J ^E1 , R, R ', R ", R ^* , R ^a , mentioned in the description of the letters of Formulas I-VI and XIA-XIV, R ^b and R ^c ) are each independently —NH ₂ , —NH (C ₁ -C ₆ alkyl) or —N (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each halogen, cyano, Hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy optionally and independently substituted with one or more substituents independently selected from the group consisting of; And the carboxy groups mentioned in the description of the characters of XIA to XIV (e.g., R ⁶ , R ⁷ , J ^E1 , R, R ', R ", R ^* , R ^a , R ^b and R ^c ) are each independently a _{-C (O) O (C 1} -C 6 alkyl), and _{-OC (O) (C 1 -C} 6 alkyl), or -CO ₂ H, wherein said alkyl groups are each halogen, Cyano, hydroxy, _{oxo, -NH 2, -NH (C 1} -C 4 alkyl), -N (C ₁ -C _{4 alkyl) 2, -OCO (C 1 -C} 4 alkyl), -CO (C ₁ Optionally and independently substituted with one or more substituents independently selected from the group consisting of -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy; Amido groups (e.g., R ⁶ , R ⁷ , J ^E1 , R, R ', R ", R ^* , R ^a , R ^b and mentioned in the description of the letters of formulas I to VI and XIA to XIV R ^c ) are each independently —NHC (O) (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ or -C (O) NH ₂ , wherein the alkyl groups are halogen, cyano, hydroxy, oxo, respectively , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), Optionally and independently substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkoxy; The aminoalkyl groups (eg R ⁸ , R ⁹ and R ″) mentioned in the description of the letters of are each independently —NH ₂ , —NH (C ₁ -C ₄ alkyl) and —N (C _1- independently from the group consisting of C ₄ alkyl) _2, And a C1-C6 alkyl group substituted with at least one amino group is selected as; Aminoalkoxy groups mentioned in the description of the letters of formulas I to VI and XIA to XIV (e.g., R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R, R 'and R ") are each independently selected from the group wherein the alkyl group is -NH ₂ , -NH (C ₁ -C ₄ alkyl) and -N (C ₁ -C ₄ alkyl) ₂ -O (C1-C6 alkyl) group substituted with one or more amino groups.

As used herein, the terms “protecting group” and “protecting group” are used interchangeably and refer to components that are used to temporarily block one or more desired functional groups in a compound having multiple reaction sites. . In certain embodiments, a protecting group has one or more of the following features, or specifically all of them: a) optionally added to the functional group in good yield to provide a protected substrate, b) the protected substrate is one It is stable to the reaction occurring at other reaction sites described above, and c) can be selectively removed in good yield by a reagent that does not attack the regenerated deprotecting functional group. As will be appreciated by those skilled in the art, in some cases, the reagents do not attack other reaction groups in the compound. In other cases, the reagent may also react with other reaction groups in the compound. Examples of protecting groups are described in Greene, TW, Wuts, PG, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, New York: 1999 (and other editions of this document). The entirety of which is incorporated herein by reference. As used herein, the term "nitrogen protecting group" refers to a component used to temporarily block one or more desired nitrogen reaction sites in a multifunctional compound. Preferred nitrogen protecting groups also have the properties exemplified for such protecting groups, and certain representative nitrogen protecting groups are also described in Chapter 7, Greene, TW, Wuts, PG, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley & Sons, New York: 1999, the entirety of which is incorporated herein by reference.

As used herein, the term "displaceable moiety" or "leaving group" means a group that is related to an aliphatic or aromatic group as defined herein and that can be translocated by nucleophilic attack by a nucleophile. do.

로 나타낸 치환체는 또한

를 나타난다.Unless specified otherwise, a structure as indicated herein is meant to include all isomeric forms of the structure (eg, enantiomers, diastereomers, cis-trans, conformational isomers and rotamers). For example, although only one isomer is specifically shown, the R and S configuration, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers for each asymmetric center are Included in As will be appreciated by those skilled in the art, the substituents can freely rotate around any rotatable bond. For example,

Substituents represented by

Appears.

Accordingly, enantiomers, diastereomers, cis / trans, morphomers and rotamer mixtures as well as single stereochemical isomers of the compounds of the present invention are within the scope of the present invention.

Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless indicated otherwise, the structures shown herein also mean including compounds in which the only difference is the presence of one or more isotope rich atoms. For example, compounds having the structure of the present invention are also within the scope of the present invention except that hydrogen is replaced by deuterium or tritium or carbon is replaced by ¹³ C- or ¹⁴ C-rich carbon. For example, R ² corresponds to formula I to VI having a -D at a position on the (e.g., Formula I, IA, II, III, IV, V and VI) and formula XIA to XIV (for example, formula XIA, XIB, Compounds of XIIA, XIIB, XIII and XIV) also fall within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium homologues, may also be useful for treatment.

The terms "bond" and "member" are used interchangeably and indicate that no group is present.

Compounds of the present invention are defined herein by their chemical structures and / or chemical names. If a compound is referred to by both its chemical structure and chemical name and the chemical structure and chemical name conflict, the chemical structure is the determining factor in compound identification.

Pharmaceutically acceptable salts, solvates, clathrates, prodrugs and other derivatives

The compounds described herein may exist in free form, or as salts where appropriate. Pharmaceutically acceptable these salts are of particular interest because they are useful for administering the compounds described below for medical purposes. Pharmaceutically unacceptable salts are useful in the manufacturing process, for isolation and purification purposes, and in some cases for the separation of stereoisomeric forms of the compounds of the invention or intermediates thereof.

As used herein, the term "pharmaceutically acceptable salt" is used in contact with tissues of humans and lower animals at reasonable benefit / harm ratios without reasonable side effects such as toxicity, irritation, allergic reactions, and the like within reasonable medical judgments. Mean salts of compounds suitable for the following.

Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail, which is incorporated herein by reference. do. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

When the compounds described herein contain a basic group or a sufficiently basic bioisostere, the acid addition salts can be prepared by 1) reacting the purified compound in free base form with a suitable organic or inorganic acid, and 2) Can be prepared by isolating the formed salt. In practice, acid addition salts may be more convenient to use, and the use of salts is the same as the use of free base forms.

Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids and amino groups such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid together. Salts formed, or salts formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, Cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate, heptanate, hexanate, hydrochloride , Hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfone Acid salts, nicotinate, nitrate, oleate, oxalate, palmitate, pamolate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propion Salts, include the acid salts, stearic acid salts, succinic acid salts, sulfate, tartrate, thio cyanate, such as, p- toluenesulfonic acid, undecane acid, valeric acid.

If the compounds described herein contain carboxy groups or sufficiently acidic bioisotopes, the base addition salts can be prepared by: 1) reacting the purified compound in acid form with a suitable organic or inorganic base, and 2) the salt thus formed. By isolating. In practice, the use of base addition salts may be more convenient, and the use of the salt form is essentially the same as the use of the free acid form. Salts derived from suitable bases include alkali metal (eg sodium, lithium and potassium) salts, alkaline earth metal (eg magnesium and calcium) salts, ammonium salts and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen-containing group of the compounds described herein. This quaternization can yield a water soluble or oil soluble or water dispersible or oil dispersible product.

Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium salts, potassium salts, calcium salts, barium salts, zinc salts, magnesium salts and aluminum salts. Sodium salts and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternized ammonium and amine cations such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. Salts formed by use with counter ions are included. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines that are frequently used in medical chemistry because of their low toxicity and allowability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, di Ethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

Other acids and bases can be used to prepare salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts, although they are not themselves pharmaceutically acceptable. Can be.

It is to be understood that the present invention may also include mixtures / combinations of different pharmaceutically acceptable salts and also mixtures / combinations of compounds and pharmaceutically acceptable salts in free form.

In addition to the compounds described herein, pharmaceutically acceptable solvates (eg hydrates) and clathrates of these compounds may also be used in the compositions to treat or prevent the disorders identified herein.

As used herein, the term "pharmaceutically acceptable solvate" is a solvate formed in which one or more pharmaceutically acceptable solvent molecules are associated with one of the compounds described herein. The term solvate includes hydrates such as hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and the like.

As used herein, the term “hydrate” means a compound described herein, or a salt thereof, further comprising a stoichiometric or non stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein, the term "inclusion compound" means a compound described herein or a salt thereof in the form of a crystal lattice containing a space (eg, a channel) in which guest molecules (eg, solvents or water) are collected. .

In addition to the compounds described herein, pharmaceutically acceptable derivatives or prodrugs of these compounds may also be used in the compositions to treat or prevent the disorders identified herein.

A “pharmaceutically acceptable derivative or prodrug” is any of the compounds described herein that, when administered to a recipient, can directly or indirectly provide a compound described herein or an inhibitory active metabolite or residue thereof. Pharmaceutically acceptable esters, salts of esters or other derivatives thereof or salts thereof. Particularly advantageous derivatives or prodrugs increase the bioavailability of the compounds of the invention when administered to a patient (e.g., by making orally administered compounds easier to absorb into the blood), or to the parent species. To enhance the delivery of the parent compound to a biological compartment (eg brain or lymphatic system).

As used herein, the term “prodrug”, unless stated otherwise, is a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted to provide a compound described herein under biological conditions (in vitro or in vivo). Means. Prodrugs may be active when reacted under these biological conditions, or they may be active in unreacted form. Examples of prodrugs contemplated herein include, but are not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate homologues. Homologs or derivatives of the compounds of the present invention comprising the same biohydrolyzable moieties are included. Other examples of prodrugs include derivatives of the compounds described herein, including -NO, -NO ₂ , -ONO or -ONO ₂ residues. Prodrugs are commonly described in well-known methods, for example BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed). It can be prepared using the method or the like.

A “pharmaceutically acceptable derivative” is an adduct or derivative that, when administered to a patient in need thereof, can directly or indirectly provide a compound or metabolite or residue thereof as described elsewhere herein. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.

Pharmaceutically acceptable prodrugs of the compounds described herein include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

Pharmaceutical composition

The compounds described herein may be formulated in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the invention described herein and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the invention is a pharmaceutical composition comprising an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected for the desired dosage form and consistent with conventional pharmaceutical practice.

"Effective amount" includes "therapeutically effective amount" and "prophylactically effective amount". The term “therapeutically effective amount” means an amount effective to treat and / or alleviate influenza virus infection in a patient infected with influenza. The term “prophylactically effective amount” means an amount effective to prevent influenza virus infection and / or substantially reduce the likelihood or magnitude of an influenza virus infection epidemic. Embodiments of effective amounts are detailed in the section entitled 'Uses of Listed Compounds'.

Pharmaceutically acceptable carriers may contain inert ingredients that do not excessively inhibit the biological activity of the compounds. Pharmaceutically acceptable carriers should be biocompatible, for example, nontoxic, non-inflammatory or non-immune, or free of other unwanted reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques can be used.

As used herein, pharmaceutically acceptable carriers, adjuvants or vehicles include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, suitable for the particular dosage form desired. Solid binders, lubricants and the like. Various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation are described in Remington's Pharmaceutical Sciences, 16th Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980). ]. Conventional carrier media may not be compatible with the compounds described herein by causing any undesirable biological effects or interacting in a deleterious manner with any other component (s) of the pharmaceutically acceptable composition. Except in cases, the use of conventional carrier media is contemplated as being within the scope of this invention. As used herein, the term "side effect" includes unwanted and negative effects of a therapeutic agent (eg, a prophylactic or therapeutic agent). Side effects are always unwanted effects, but unwanted effects are not necessarily negative. Negative effects from therapy (eg, prophylactic or therapeutic) can be harmful, unpleasant or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including stomach and intestinal ulcers and erosion), nausea, vomiting, neurotoxicity, nephrotoxicity, kidney toxicity (papillary necrosis and chronic interstitial nephritis) Condition), liver toxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including white blood cell reduction, myelosuppression, platelet reduction and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, drowsiness, pain (muscle pain, bone pain) And headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, inability to sit, cardiovascular disorders and sexual dysfunction.

Some examples of materials that can act as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg human serum albumin), buffer substances (eg twin) 80, including phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts, colloids Soluble silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, methylcellulose, hydroxypropyl methylcellulose, wool; Sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Celluloses and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol or polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogenic material removal water; Isotonic saline; Ringer's solution; Ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, mold release agents, coatings, sweeteners, flavoring and flavoring agents, preservatives and oxidation An inhibitor may also be present in the composition at the discretion of the formulator.

Dosing method

The compounds and pharmaceutically acceptable compositions described above may vary depending on the severity of the infection to be treated, oral, rectal, parenteral, intravenous, intravaginal, intraperitoneal, topical (as a powder, ointment or drop), oral cavity ( Orally or as a nasal spray), or the like.

Oral liquid dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microfluids, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofur Fatty acid esters of furyl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions or emulsions, such as solutions in 1,3-butanediol, parenterally acceptable non-toxic diluents or solvents. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose any bland nonvolatile oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are also used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial manure filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media before use. .

In order to sustain the efficacy of the compounds described herein, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injection formulations are also prepared by entrapping the compound in liposomes or microfluids that are compatible with body tissues.

Compositions for rectal or vaginal administration are specifically suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository waxes, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compounds. Are suppositories that can be prepared by mixing with the compounds described herein.

Solid dosage forms for oral use include capsules, tablets, pills, powders, and granules. In such solid dosage forms the active compound is prepared by one or more pharmaceutically acceptable inert excipients or carriers such as sodium citrate or dicalcium phosphate and / or a) fillers such as starch, lactose, sucrose, glucose, mannitol and silicic acid or Extenders, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) agar, calcium carbonate, potatoes or tapioca starch, alginic acid, certain silicates And disintegrants such as sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as kaolin and bentonite clay And i) talc, calcium stearate, magnesium stearate, solid polyethylene glyco , It referred to us mixed with lubricants, such as sodium sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally comprise an opacifying agent, which may also be a composition which releases the active substance (s) uniquely or predominantly in certain parts of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

The active compounds may also be present in microencapsulated form with one or more excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms the active compound may be admixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also include additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as in conventional practice. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. They may optionally comprise an opacifying agent, which may also be a composition which releases the active substance (s) uniquely or predominantly in certain parts of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Topical or transdermal dosage forms of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated as being within the scope of this invention. In addition, the present invention encompasses the use of transdermal patches having the additional advantage of providing controlled delivery of a compound into the body. Such dosage forms are made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions described herein can be administered via oral, parenteral, inhalational spray, topical, rectal, nasal, oral, vaginal or transplant reservoirs. As used herein, the term “parenteral” includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarterial, synovial, intrasternal, spinal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Include. In particular, the composition is administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic diluent or solvent that can be parenterally administered, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Sterile, nonvolatile oils are also conventionally employed as a solvent or suspending medium. For this purpose, any non-irritating nonvolatile oil can be used including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and their glyceride derivatives are useful for the preparation of injectable preparations, as well as pharmaceutically acceptable natural oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may contain long chain alcohol diluents or dispersants, such as carboxymethyl cellulose, or similar dispersants conventionally used in the formulation of pharmaceutically acceptable dosage forms comprising emulsions and suspensions. Other commonly used surfactants such as tween and span and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for the purpose of formulating.

The pharmaceutical compositions described herein can be administered orally in any dosage form that can be administered orally, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricants such as magnesium stearate are usually added. Diluents useful for oral administration in capsule form include lactose and dried corn starch. If an oral aqueous suspension is required, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of rectal suppositories. They can be prepared by mixing the components with a suitable non-irritating vehicle that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions described herein may be administered topically, especially if the target of the treatment comprises a site or organ that is easily accessible by topical application, such as a disease of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these sites or organs.

Topical application for the lower intestine may be effective for rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

For topical administration, the pharmaceutical compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For intraocular use, the pharmaceutical compositions are formulated as a differential suspension in pH controlled isotonic sterile saline, or specifically as a solution in pH controlled isotonic sterile saline, with or without preservatives such as benzylalkonium chloride. Can be converted. Alternatively, for intraocular use, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions can also be administered by nasal aerosol or inhalation. These compositions are prepared according to techniques well known in the pharmaceutical formulating art, and are brine using benzyl alcohol or other suitable preservatives, absorption accelerators to increase bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants. It can be prepared as a solution in.

Compounds for use in the methods of the invention may be formulated in unit dosage forms. The term "unit dosage form" refers to physically discrete units suited as unitary dosages for the subjects to be treated, each unit being calculated to provide the desired therapeutic effect, optionally with a suitable pharmaceutical carrier. Contains a predetermined amount of active substance. The unit dosage form may be one dose per day or one of multiple doses per day (eg, about 1 to 4 or more times per day). If multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Example

Preparation of the compound

Herein comprising compounds of Formulas I-VI (e.g., Formulas I, IA, II, III, IV, V, and VI) and Formulas XIA-XIV (e.g., Formulas XIA, XIB, XIIA, XIIB, XIII, and XIV) The compounds described in the specification can be prepared by any suitable method known in the art, for example WO 2005/095400 and WO 2007/084557. For example, the compounds shown in FIGS. 3A-8B can be prepared by any suitable method known in the art, for example, by WO 2005/095400 and WO 2007/084557 and the exemplary synthesis methods described below. Can be prepared. In particular, the compounds shown in FIGS. 8A and 8B can be prepared as described in WO 2005/095400 and WO 2007/084557. Hereinafter, the synthesis of certain exemplary compounds of Formulas I-VI and XIA-XIV is described. In general, the compounds of formulas I-VI and XIA-XIV may be prepared as shown in these synthesis methods, optionally with any desired suitable modifications.

General analysis method

As used herein, the term RT (min) refers to the LCMS retention time in minutes associated with the compound. Unless otherwise specified, the method used to obtain the reported residence time is as follows:

Column: YMC-Pack Pro Cig, 50 mm x 4.6 mm id

Gradient: 10-95% methanol / H ₂ O. Flow rate: 1.5 mL / min. UV-vis detection.

Synthesis and Identification of Compounds

Hereinafter, certain exemplary compounds of Formulas I to VI (e.g., Formulas I, IA, II, III, IV, V and VI) and Formulas XIA to XIV (e.g., Formulas XIA, XIB, XIIA, XIIB, XIII and XIV) Describe the synthesis of these. NMR and mass spectrometry data of certain specific compounds are summarized in Tables 1-5.

Scheme 1

(a) (S) -1-Boc-3-aminopiperidine, ⁱ Pr ₂ NEt, DMF, 90 ° C .; (b) TFA, CH ₂ Cl ₂ (c) 2- (methoxymethyl) oxirane, EtOH, microwave, 140 ° C. (d) 1N LiOH, THF, microwave, 120 ° C.

(S) -tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) piperidine-1-carboxylate (1b)

5-Chloro-3- (5-fluoro-4-methylsulfonyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] in DMF (32 mL) Diisopropylethylamine (2.6 mL) in a solution of pyridine (1a) (3.5 g, 7.5 mmol) and tert-butyl (3S) -3-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) 15.1 mmol) was added. The reaction mixture was heated to 90 ° C. for 75 minutes. The mixture was cooled to rt, diluted with saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (0% -10% MeOH / CH ₂ Cl ₂ ) to afford the desired product 1b as a white solid.

LCMS RT = 4.6 (M + 1) 601.5, (M-1) 599.6.

(S) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyridine Formation of midin-4-amine (1c)

Tert-butyl (3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridine-3- in CH ₂ Cl ₂ (30 mL) Trifluoroacetic acid (20 mL) was added to a solution of yl] -5-fluoro-pyrimidin-4-yl] amino] piperidine-1-carboxylate (1b) (2.1 g, 3.5 mmol). The reaction mixture was stirred for 75 minutes at room temperature, then the mixture was concentrated in vacuo. The crude residue was diluted with EtOAc and neutralized with 1N sodium hydroxide solution. The aqueous phase was separated and extracted again with EtOAc. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the desired product (1c) as a pale yellow solid.

1-((S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino Formation of Piperidin-1-yl) -3-methoxypropan-2-ol (1d)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-N-[(3S) -3-piperi in ethanol To a solution of dill] pyrimidin-4-amine (1c) (0.20 g, 0.40 mmol) was added 2- (methoxymethyl) oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated to 140 ° C. for 5 minutes in a microwave reactor. The reaction was evaporated to dryness and the residue obtained was purified by silica gel chromatography (0-10% MeOH: CH ₂ Cl ₂ ) to afford the desired product (1d).

1-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine Formation of -1-yl) -3-methoxypropan-2-ol (537)

1-[(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro- in THF To a solution of pyrimidin-4-yl] amino] -1-piperidyl] -3-methoxy-propan-2-ol (1d) (0.15 g, 0.24 mmol) was added 1N LiOH solution. The reaction mixture was heated to 120 ° C. for 5 minutes in a microwave reactor. The reaction mixture was diluted with water and the aqueous phase extracted with EtOAc (twice). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The solid obtained was purified by silica gel chromatography (5-20% MeOH: CH ₂ Cl ₂ ) to afford the desired product (537) as a white solid.

Other homologues which may be prepared in the same manner as compound (537) are described below:

3-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) propane-1,2-diol (525)

1-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -3-isopropoxypropan-2-ol (551)

(S) -1-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino ) Piperidin-1-yl) butan-2-ol (538)

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2-methylpropan-2-ol (546)

(R) -3-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino ) Piperidin-1-yl) propane-1,2-diol (588)

(S) -3-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino ) Piperidin-1-yl) propane-1,2-diol (587)

1-((3S, 4S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino)- 4-methylpiperidin-1-yl) -3-methoxypropan-2-ol (550)

3-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2-hydroxypropanamide (603)

Scheme 2

(a) tert-butylbromoacetate, Na ₂ CO ₃ , DMF (b) 1N LiOH, THF, microwave, 120 ° C., 10 min (c) TFA, CH ₂ Cl ₂

(S) -tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) piperidine-1-carboxylate (2a)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-N-[(3S) -3-piperi in DMF To a solution of dill] pyrimidin-4-amine (1c) (0.25 g, 0.50 mmol) was added tert-butylbromoacetate (0.08 mL, 0.55 mmol) and Na ₂ CO ₃ (0.11 g, 0.99 mmol). . The reaction mixture was stirred at rt for 6 h. The thick white precipitate obtained was diluted with saturated aqueous NaCl solution and washed with water. The white solid was dissolved in CH ₂ Cl ₂ and the solution was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography (0% -5% MeOH / CH ₂ Cl ₂ ) to afford the desired product 2a as a white solid.

(S) -tert-butyl 2- (3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino Formation of Piperidin-1-yl) ethanoate (2b)

Tert-butyl 2-[(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5 in THF To a solution of -fluoro-pyrimidin-4-yl] amino] -1-piperidyl] acetate (2a) (0.27 g, 0.44 mmol) was added 1N LiOH solution. The reaction mixture was heated to 120 ° C. for 10 minutes in microwave. The reaction mixture was diluted with brine and extracted with EtOAc, then 20% isopropanol / CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The obtained product (2b) was used without further purification.

LCMS RT = 2.0 (M + 1) 461.5.

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine Formation of -1-yl) ethanoic acid (577)

Tert-butyl 2-[(3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5 in CH ₂ Cl ₂ (4 mL) To a solution of -fluoro-pyrimidin-4-yl] amino] -1-piperidyl] acetate (2b) (0.12 g, 0.26 mmol) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at rt for 18 h and concentrated in vacuo. The crude residue was diluted with 5% MeOH / CH ₂ Cl ₂ and the white precipitate obtained was filtered and washed with CH ₂ Cl ₂ to afford the desired product (577) as trifluoroacetic acid salt.

Other homologues which may be prepared in the same manner as compound (577):

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) ethaneamide (567)

2-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) propanamide (583)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-cyanopyrimidin-4-ylamino) piperidine -1-yl) ethaneamide (654)

LCMS RT = 2.9 (M + 1) 411.4, (M-1) 409.4.

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methylpyrimidin-4-ylamino) piperidine- 1-yl) ethaneamide (620)

LCMS RT = 1.9 (M + 1) 400.4, (M-1) 398.3.

2-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) propanoic acid (573)

2-((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -N-methylpropanamide (606)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2-methylpropanoic acid (590)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2-methylpropanamide (598)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -N, 2-dimethylpropanamide (599)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -N, N, 2-trimethylpropanamide (600)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -N- (2-methoxyethyl) -2-methylpropanamide (601)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -N-cyclopropyl-2-methylpropanamide (602)

Scheme 3

(a) CF ₃ CH ₂ SO ₂ CCl ₃ , ⁱ Pr ₂ NEt, DMF (b) 1N LiOH, THF, microwave, 120 ° C., 10 minutes

(S) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (2,2,2- Formation of Trifluoroethyl) piperidin-3-yl) pyrimidin-4-amine (3a)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-N-[(3S)-in DMF (1.5 mL) To a solution of 3-piperidyl] pyrimidin-4-amine (1c) (0.17 g, 0.34 mmol) was added 2,2,2-trifluoroethyl trichloromethanesulfonate (0.19 g, 0.68 mmol). Then ⁱ Pr ₂ NEt (0.24 mL, 1.36 mmol) was added. The reaction mixture was stirred at rt for 18 h. The mixture was poured into brine and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO ₄ ) _, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH / CH ₂ Cl ₂ ) to afford the desired product 3a as a white solid.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (2,2,2-trifluoroethyl Formation of Piperidin-3-yl) pyrimidin-4-amine (668)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-N-[(3S) -1- (2 in THF To a solution of 2,2-trifluoroethyl) -3-piperidyl] pyrimidin-4-amine (3a) (0.10 g, 0.18 mmol) was added 1 M LiOH solution (0.90 mL, 0.90 mmol). The reaction mixture was heated to 120 ° C. for 10 minutes in microwave. The reaction mixture was diluted with brine and extracted with EtOAc, then 20% isopropanol / CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (0-10% MeOH: CH ₂ Cl ₂ ) to afford the desired product (1339) as a white solid.

Other homologues that may be prepared in the same manner as compound 668:

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (2,2-difluoroethyl) piperidine-3- Synthesis of I) -5-fluoropyrimidin-4-amine (1)

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (2,2-difluoroethyl) piperidine-3- Yl) -5-fluoropyrimidin-4-amine (595)

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) ethanenitrile (669)

Scheme 4

(a) 1H-imidazole-2-carbaldehyde, Na (OAc) ₃ BH, HOAc, 1,2-dichloroethane, 60 ° C. (b) 1N LiOH, THF, microwave, 120 ° C., 10 minutes

(S) -N- (1-((1H-imidazol-2-yl) methyl) piperidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3 -b] formation of pyridin-3-yl) -5-fluoropyrimidin-4-amine (4a)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-N- in 1,2-dichloroethane (2 mL) To a solution of [(3S) -3-piperidyl] pyrimidin-4-amine (1c) (0.16 g, 0.32 mmol) was added 1H-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol). , 2 drops of acetic acid and Na (OAc) ₃ BH (0.10 g, 0.49 mmol) were added. The reaction mixture was heated to 60 ° C. for 18 hours. The mixture was cooled to rt and diluted with saturated aqueous NaHCO ₃ . The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-20% MeOH / CH ₂ Cl ₂ ) to afford product 4a.

(S) -N- (1-((1H-imidazol-2-yl) methyl) piperidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridine Formation of 3-yl) -5-fluoropyrimidin-4-amine (589)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-N-[(3S)-in THF (2.5 mL) To a solution of 1- (1H-imidazol-2-ylmethyl) -3-piperidyl] pyrimidin-4-amine (4a) (0.08 g, 0.13 mmol) was added 1 M LiOH solution (0.67 mL, 0.65 mmol). The reaction mixture was heated to 120 ° C. for 10 minutes in microwave. The mixture was cooled to rt and diluted with brine. The aqueous phase was extracted with CH ₂ Cl ₂ and then _twice with 20% isopropanol / CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the desired product (589) as a white solid.

Other homologues which may be prepared in the same manner as compound (589):

N- (1-((1H-imidazol-5-yl) methyl) piperidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl ) -5-fluoropyrimidin-4-amine (594)

Scheme 5A

(a) tert-butyl (3S) -3-aminopiperidine-1-carboxylate, ⁱ Pr ₂ NEt base, 2-propanol, 80 ° C. (b) 5-chloro-1- (p-tolylsulfonyl ) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine, DME / H ₂ O, K ₂ CO ₃ , tetrakis triphenylphosphinepalladium (0), 90 ° C. (c) NaOMe / MeOH (d) isopropanol / HCl (e) methanesulfonyl chloride, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

Formation of tert-butyl (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] piperidine-1-carboxylate (5a)

Tert-butyl (3S) -3-aminopiperidine-1-carboxylate (8.1 g, 40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, in isopropanol (80 mL) 39.8 mmol) was added N, N-diisopropyl-N-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80 ° C. and stirred for 17 h. All volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers separated. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The obtained residue was dissolved in CH ₂ Cl ₂ and purified by silica gel chromatography (0-50% EtOAc / hexanes) to afford the desired product (5a).

LCMS RT = 3.3 (M + 1) 331.1.

Tert-butyl (3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-pyri Midin-4-yl] amino] piperidine-1-carboxylate (1b)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxa in DME (15 mL) and H ₂ O (5 mL) Borola-2-yl) pyrrolo [2,3-b] pyridine (1.8 g, 4.2 mmol) and tert-butyl (3S) -3-[(2-chloro-5-fluoro-pyrimidine-4 To a solution of -yl) amino] piperidine-1-carboxylate (5a) (1.2 g, 3.7 mmol) was added K ₂ CO ₃ (1.7 g, 12.1 mmol). The mixture was purged with nitrogen for 15 minutes. Tetrakis triphenylphosphine palladium (0) (0.2 g, 0.2 mmol) was added to the mixture and the reaction mixture was heated to 90 ° C. for 3 days. The reaction was cooled to rt and then diluted with EtOAc / H ₂ O. The layers were separated and the organic phase was washed with brine, dried (MgSO ₄ ), filtered and evaporated to dryness. The residue obtained was dissolved in CH ₂ Cl ₂ and purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the desired product 1b.

LCMS RT = 4.6 (M + 1) 601.2.

Tert-butyl (3S) -3-[[2- (5-chloro-lH-pyrrolo [5,4-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino ] Formation of piperidine-1-carboxylate (2b)

Tert-butyl (3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl]-in methanol (10 mL) To a solution of 5-fluoro-pyrimidin-4-yl] amino] piperidine-1-carboxylate (1b) (0.93 g, 1.55 mmol) was added sodium methoxide (10 mL of 1M solution). The reaction mixture was raised to 45 ° C. After stirring for 30 minutes, the reaction was cooled to room temperature and quenched by addition of water. The mixture was diluted with EtOAc and the layers separated. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the desired product (2b).

LCMS RT = 2.8 (M + 1) 447.2.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidine-4- Formation of Amine 5b

Tert-butyl (3S) -3-[[2- (5-chloro-lH-pyrrolo [5,4-b] pyridin-3-yl) -5-fluoro-pyrimidine in isopropanol (3 mL) To a suspension of -4-yl] amino] piperidine-1-carboxylate (2b) (0.45 g, 1.01 mmol) was added propan-2-ol hydrochloride (1.5 mL of 5M solution, 7.500 mmol). The reaction mixture was warmed to 80 ° C. and stirred for 3 hours. The mixture was cooled to room temperature and all volatiles were removed at reduced pressure. The crude product 5b obtained was used without further purification.

LCMS RT = 1.5 (M + 1) 347.1.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (methylsulfonyl) piperidine-3- (1) Formation of Pyrimidin-4-amine (389)

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N in CH ₂ Cl ₂ (1.4 mL) and DMF (0.30 mL) N, N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) in a solution of (piperidin-3-yl) pyrimidin-4-amine hydrochloride (5b) (0.04 g, 0.11 mmol) After addition, methanesulfonyl chloride (0.02 g, 0.20 mmol) was added. The reaction mixture was stirred at rt for 17 h. The mixture was concentrated in vacuo, dissolved in 1 mL DMSO and purified by preparative HPLC (0.1% ammonium formate-H ₂ O / acetonitrile) to afford the desired product (389).

LCMS RT = 1.8 (M + 1) 425.3.

Other homologues which may be prepared in the same manner as compound (389):

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (ethylsulfonyl) piperidin-3-yl) -5- Fluoropyrimidin-4-amines (393)

LCMS RT = 1.8 (M + 1) 439.3.

(S) -N- (1- (butylsulfonyl) piperidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5- Fluoropyrimidin-4-amines (390)

LCMS RT = 2.1 (M + 1) 467.3.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopropylsulfonyl) piperidin-3-yl) -5 -Fluoropyrimidin-4-amines (391)

LCMS RT = 1.9 (M + 1) 451.3.

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (isopropylsulfonyl) -piperidine- 3-yl) pyrimidin-4-amine (394)

LCMS RT = 1.9 (M + 1) 453.3.

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopentylmethylsulfonyl) piperidin-3-yl)- 5-fluoropyrimidin-4-amine (392)

LCMS RT = 2.3 (M + 1) 493.5.

Scheme 5B

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) piperidine-3- (1) Formation of Pyrimidin-4-amine (316)

CH ₂ Cl ₂ / DMF (8 mL) 2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (piperi in a 10: 1 mixture -3-yl) pyrimidin-4-amine (5c) (0.40g, 1.15mmol) solution in _{^{i Pr 2 NEt (0.60㎖, 3.46mmol}} ) for the addition, 1-propane sulfonyl chloride (0.13㎖ of , 1.15 mmol) was added. The reaction mixture was stirred at rt for 5 h. The residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product 316.

LCMS RT = 2.5 (M + 1) 453.3.

Other homologues which may be prepared in the same manner as compound 316:

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (ethylsulfonyl) piperidin-3-yl) -5- Fluoropyrimidin-4-amines (321)

LCMS RT = 2.7 (M + 1) 439.1.

(R) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (isopropylsulfonyl) -piperidine- 3-yl) pyrimidin-4-amine (322)

LCMS RT = 2.9 (M + 1) 453.1.

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) -piperidine-3 -Yl) pyrimidin-4-amine (306)

LCMS RT = 2.9 (M + 1) 453.2.

Scheme 5C

(a) cyclobutanecarbonyl chloride, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

(S)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 -Yl) (cyclobutyl) methanone (395) formation

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N in CH ₂ Cl ₂ (1.40 mL) and DMF (300 μL) N, N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) in a solution of (piperidin-3-yl) pyrimidin-4-amine hydrochloride (5b) (0.04 g, 0.11 mmol) After addition, cyclobutanecarbonyl chloride (0.01 g, 0.12 mmol) was added. The reaction mixture was stirred at rt for 17 h. The mixture was concentrated in vacuo, dissolved in 1 mL DMSO and purified by preparative HPLC (0.1% ammonium formate-H ₂ O / acetonitrile) to afford the desired product (395).

LCMS RT = 1.9 (M + 1) 429.3.

Other homologues which may be prepared in the same manner as compound (395):

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) propane-1-one (435)

LCMS RT = 1.8 (M + 1) 403.4.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2-methylpropan-1-one (436)

LCMS RT = 1.9 (M + 1) 417.4.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2,2-dimethylpropan-1-one (437)

LCMS RT = 2.0 (M + 1) 431.4.

(S)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 -Yl) (cyclopropyl) methanone (451)

LCMS RT = 1.8 (M + 1) 415.4.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -3-methoxypropan-1-one (396)

LCMS RT = 1.7 (M + 1) 433.3.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) ethanone (434)

LCMS RT = 1.6 (M + 1) 389.4.

(R) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -3-methylbutan-1-one (318)

LCMS RT = 2.9 (M + 1) 431.1.

(R)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 -Yl) (cyclopropyl) methanone (317)

LCMS RT = 2.7 (M + 1) 415.1.

(R) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -3-methoxypropan-1-one (320)

LCMS RT = 2.5 (M + 1) 433.1.

(R)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 -Yl) (cyclobutyl) methanone (319)

LCMS RT = 2.8 (M + 1) 429.1.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -3-methylbutan-1-one (332)

LCMS RT = 2.0 (M + 1) 431.2.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) piperidin-1-yl) Ethanone (485)

LCMS RT = 1.9 (M + 1) 371.5.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -2-methoxyethanone (486)

LCMS RT = 1.9 (M + 1) 401.5.

(S) -methyl 4- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) piperidin-1-yl ) -4-oxobutanoate (487)

LCMS RT = 2.0 (M + 1) 443.9.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine -1-yl) -3-methoxypropan-1-one (488)

LCMS RT = 1.9 (M + 1) 415.5.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) piperidin-1-yl) -3-methylbutan-1-one (489)

LCMS RT = 2.1 (M + 1) 413.5.

Scheme 5D

(a) 1-methylcyclopropane-1-carboxylic acid, EDAC-HCl, HOBt, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

(S)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 -Yl) (1-methylcyclopropyl) methanone 445

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N in CH ₂ Cl ₂ (1.4 mL) and DMF (0.3 mL) N, N-diisopropyl-N-ethylamine (0.3 mL, 1.72 mmol) in a solution of (piperidin-3-yl) pyrimidin-4-amine hydrochloride (5b) (0.04 g, 0.10 mmol) 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (0.02 g, 0.12 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.12 mmol) after addition ) And 1-methylcyclopropane-1-carboxylic acid (0.01 g, 0.12 mmol) were added. The mixture was concentrated in vacuo, dissolved in 1 mL DMSO and purified by preparative HPLC (0.1% ammonium formate-H ₂ O / acetonitrile) to afford the desired product 445.

LCMS RT = 2.1 (M + 1) 429.5.

Homologs which may be prepared in the same manner as compound 445:

(S)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 -Yl) (3-methyloxetan-3-yl) methanone (444)

LCMS RT = 1.7 (M + 1) 445.4.

Scheme 5E

(a) isocyanatopropane, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-isopropylpy Formation of Ferridine-1-carboxamide (439)

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N in CH ₂ Cl ₂ (1.4 mL) and DMF (0.3 mL) N, N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) in a solution of (piperidin-3-yl) pyrimidin-4-amine hydrochloride (5b) (0.042 g, 0.100 mmol) After addition, isocyanatopropane (0.120 mmol) was added. The reaction mixture was stirred at rt for 17 h. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparative HPLC (0.1% ammonium formate-H ₂ O / acetonitrile) to afford the desired product (439).

LCMS RT = 1.8 (M + 1) 432.4.

Other homologs which may be prepared in the same manner as compound (439):

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-ethylpiperi Dean-1-carboxamide (438)

LCMS RT = 1.7 (M + 1) 418.4.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-propylpiperidine-1- Formation of Carboxamide 196

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (pi in a 1: 1 mixture (2 mL) of CH ₂ Cl ₂ / pyridine. To a solution of ferridin-3-yl) pyrimidin-4-amine (5b) (0.020 g, 0.058 mmol) was added propyl isocyanate (0.005 mL, 0.058 mmol). The reaction mixture was stirred at rt for 12 h. The residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product 196.

LCMS RT = 2.6 (M + 1) 432.1, (M-1) 430.1.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-propylpiperi Dean-1-carboxamide (324)

LCMS RT = 2.6 (M + 1) 432.2.

(S) -N-butyl-3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperi Dean-1-carboxamide (323)

LCMS RT = 2.7 (M + 1) 446.2.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1- Carboxamide (507)

LCMS (TFA buffer): Rt 1.69 min, ES ⁺ 390.

Scheme 5F

(a) Methylchloroformate, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

(S) -methyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 Formation of carboxylate 440

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N in CH ₂ Cl ₂ (1.4 mL) and DMF (0.3 mL) N, N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) in a solution of (piperidin-3-yl) pyrimidin-4-amine hydrochloride (5b) (0.042 g, 0.100 mmol) After addition, methyl chloroformate (0.009 g, 0.120 mmol) was added. The reaction mixture was stirred at rt for 17 h. The mixture was concentrated in vacuo, dissolved in 1 ml of DMSO and purified by preparative HPLC (0.1% ammonium formate-H ₂ O / acetonitrile) to afford the desired product 440.

LCMS RT = 1.8 (M + 1) 405.4.

Homologs which may be prepared in the same manner as compound 440:

(S) -Ethyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1 Carboxylate 441.

LCMS RT = 1.9 (M + 1) 419.4.

(S) -Isopropyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine- 1-carboxylate (442)

LCMS RT = 2.1 (M + 1) 433.4.

Scheme 5G

(a) (2,5-dioxopyrrolidin-1-yl) [(3S) -tetrahydrofuran-3-yl] carbonate, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

(S)-((S) -tetrahydrofuran-3-yl) 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyripy Formation of midin-4-ylamino) piperidine-1-carboxylate (443)

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N in CH ₂ Cl ₂ (1.4 mL) and DMF (0.3 mL) N, N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) in a solution of (piperidin-3-yl) pyrimidin-4-amine hydrochloride (5b) (0.042 g, 0.100 mmol) After addition, (2,5-dioxopyrrolidin-1-yl) [(3S) -tetrahydrofuran-3-yl] carbonate (0.028 g, 0.120 mmol) was added. The reaction mixture was stirred at rt for 17 h. The mixture was concentrated in vacuo, dissolved in 1 mL DMSO and purified by preparative HPLC (0.1% ammonium formate-H ₂ O / acetonitrile) to afford the desired product 443.

LCMS RT = 1.8 (M + 1) 463.3.

Scheme 6A

(a) ⁱ Pr ₂ NEt, THF (b) Pd (PPh ₃ ) ₄ , 2M Na ₂ CO ₃ 80 ° C. (c) 4N HCl / dioxane, MeOH, 80 ° C. (d) (S) -2,5- Dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate, ⁱ Pr ₂ NEt, THF (e) 25% NaOMe / MeOH or 1M LiOH, 150 ° C., microwave, 10 min.

Formation of tert-butyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -cyclobutylcarbamate (6a)

A mixture of 2,4-dichloro-5-fluoro-pyrimidine (0.97 g, 5.81 mmol) and ⁱ Pr ₂ NEt (2.53 mL, 14.50 mmol) in THF (50 mL) was added tert-butyl 3-aminoazetidine Treated with -1-carboxylate (1.00 g, 5.81 mmol) and stirred at room temperature until completeness was confirmed by LCMS. The mixture was concentrated to dryness, then diluted with water and extracted with dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to afford an oil, which was purified by silica gel chromatography (0-100% petroleum ether / EtOAc gradient). The solvent was removed under reduced pressure and dried in vacuo to yield 3.36 g (89% yield) of a white solid.

LCMS: RT = 3.2 min, ES ⁺ 303.

Tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine Formation of -1-carboxylate (6b)

Tert-butyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -cyclobutylcarbamate (6a) (0.39 g in DME (10 mL) and 2M Na ₂ CO ₃ (5 mL) , 1.28 mmol) and 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2, 3-b] pyridine (0.60 g, 1.39 mmol) was degassed with argon (vacuum and refilled three times), then treated with catalyst Pd (PPh ₃ ) ₄ and the mixture was heated to 80 ° C. under argon. After 3 hours, the solvent was concentrated to reduce the volume, then diluted with EtOAc, filtered through florisil (40 mL pad) and washed with EtOAc. The solvent was concentrated in vacuo and the dark residue obtained was purified by silica-gel chromatography (0-100% petroleum ether / EtOAc gradient) to give 230 mg (32%) of compound 6b as a white-pink solid. It was.

LCMS: RT = 4.7 min, ES ⁺ 573.

N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine Formation of hydrochloride (6c)

Tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 in methanol (10 mL) A suspension of -ylamino) azetidine-1-carboxylate (6b) (0.23 g, 0.40 mmol) was treated with 4N HCl / dioxane (5 mL, 20 mmol) and then heated to 80 ° C. for 30 minutes. The solvent was removed and the residue was dried in vacuo to give 240 mg of solid, which was used without purification.

LCMS RT = 2.4 min, ES ⁺ 473.

(S) -tetrahydrofuran-3-yl 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino Formation of Azetidine-1-carboxylate (422)

N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in THF (1 mL) A suspension of pyrimidin-4-amine hydrochloride (6c) (0.06 g, 0.11 mmol) was treated with ⁱ Pr ₂ NEt (0.30 mL, 1.70 mmol) and then solid (S) -2,5-dioxopyrrolidine -1-yl tetrahydrofuran-3-yl carbonate (0.03 g, 0.11 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, then quenched with 200 mL of morpholine and evaporated to dryness (S) -tetrahydrofuran-3-yl 3- (2- (5-chloro-1-tosyl-1H -Pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxylate (6d) was obtained, which was used without purification.

LCMS RT = 3.8 min, ES ⁺ 588.

(S) -tetrahydrofuran-3-yl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- 4-ylamino) azetidine-1-carboxylate (6d) was dissolved in methanol (2 mL), then treated with 25% sodium methoxide / methanol (0.5 mL) and heated to 60 ° C. in a closed tube. . After 10 minutes LCMS showed a complete reaction. The resulting solution was quenched with saturated aqueous NH ₄ Cl solution (0.5 mL), then evaporated to dryness, the residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to give 25.9 mg of the desired product (422) (yield). 55%) was obtained as a solid.

LCMS RT = 1.8 min, ES ⁺ 433.

Scheme 6B

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) azetidin-3-yl Formation of Pyrimidin-4-amine (423)

N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in THF (1 mL) To the stirred suspension of pyrimidin-4-amine hydrochloride (6c) (0.055 g, 0.110 mmol) was added ⁱ Pr ₂ NEt (0.300 mL, 1.720 mmol) followed by propane-1-sulfonyl chloride (0.012 mL, 0.108). mmol) was added. The homogeneous pale yellow solution mixture obtained was heated to 50 ° C. for 1 h, at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution was evaporated to dryness. The residue obtained was dissolved in methanol (2 mL), then treated with 25% sodium methoxide / methanol (0.5 mL) and heated to 60 ° C. for 10 min in a closed tube. The resulting solution was quenched with saturated aqueous NH ₄ Cl solution (0.5 mL) and then evaporated to dryness. The residue obtained was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to give 19.8 mg (43%) of the desired product (423) as a solid.

LCMS RT = 2.6 min, ES ⁺ 425.

Other homologues that may be prepared in a similar manner to compound 423:

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopentyl-methylsulfonyl) azetidin-3-yl) -5-fluoro Formation of Pyrimidin-4-amine (469)

N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in dichloromethane (1 mL) a pyrimidin-4-amine hydrochloride (6c) after addition of _{^{i Pr 2 NEt (0.33㎕, 1.90mmol}} ) to a stirred solution of (0.03g, 0.06mmol), cyclopentyl methanesulfonyl chloride (0.01g, 0.06 mmol) was added. The resulting mixture was stirred at rt for 30 min, at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution was evaporated to dryness. The residue obtained was dissolved in methanol (2 mL), then treated with 25% sodium methoxide / methanol (0.5 mL) and heated to 60 ° C. for 10 min in a closed tube. The solution was quenched with saturated aqueous NH ₄ Cl solution (0.5 mL) and then evaporated to dryness. The residue obtained was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to give 27.4 mg (88% yield) of the desired product (469) as a solid.

LCMS RT = 3.1 min, ES ⁺ 465.

1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidin-1-yl) Formation of 2-methoxyethanone 468

According to the method for compound (469), 11.7 mg (yield 51%) of compound (468) was obtained using methoxyacetyl chloride as a white solid.

LCMS RT = 1.6 min, ES ⁺ 390.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxamide (512 Formation of

87 mg (79% yield) of compound (512) as a white solid using 61 mg (0.11 mmol) of compound (6c) and isocyanatotrimethylsilane (15.14 μl, 0.11 mmol) according to the method for compound (469) Obtained.

LCMS RT = 2.4 min. ES ⁺ 362.

Scheme 7

(a) 2,4-dichloro-5-fluoropyrimidine, ⁱ Pr ₂ NEt, THF (b) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, Pd (PPh ₃ ) ₄ , 2M Na ₂ CO ₃ 90 ° C. (c) 4N HCl / dioxane, MeOH 80 ° C .; (d) methanesulfonyl chloride, ⁱ Pr ₂ NEt, THF, RT (e) 25% NaOMe / MeOH or 1M LiOH, 150 ° C., microwave, 10 min.

Formation of (S) -tert-butyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylate (7a)

Tertiary in THF (2 mL) in a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.75 g, 10.48 mmol) and ⁱ Pr ₂ NEt (3.27 mL, 18.78 mmol) in THF (50 mL) Butyl (3S) -3-aminopyrrolidine-1-carboxylate (1.83 mL, 10.48 mmol) was added. The resulting solution was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to afford 3.41 g of compound (7a) as a white foamy solid.

LCMS RT = 3.0 min. ES ⁺ 317.

(S) -tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) pyrrolidine-1-carboxylate (7b)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2- in DME (34 mL) and 2M Na ₂ CO ₃ (8.5 mL) Dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (2.41 g, 5.60 mmol) and tert-butyl (3S) -3-[(2-chloro-5-fluoro-pyrimidine A solution of -4-yl) amino] pyrrolidine-1-carboxylate (7a) (1.69 g, 5.30 mmol) was degassed with nitrogen (5 minutes), followed by Pd (PPh ₃ ) ₄ (0.31 g, 0.27 mmol). ), Then heated to 90 ° C. overnight. The dark solution obtained was filtered through Florisil, washed with EtOAc and then concentrated in vacuo. The residue obtained was purified by silica-gel chromatography (0-100% petroleum ether: EtOAc gradient). The solvent was removed under reduced pressure and dried in vacuo to yield 1.33 g (42% yield) of a white solid.

LCMS RT = 4.4 min, ES ⁺ 588.

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-N-[(3S) -pyrrolidine-3- Formation of Pyrimidin-4-amine (7c)

Tert-butyl (3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl]-in THF (25 mL) A solution of 5-fluoro-pyrimidin-4-yl] amino] pyrrolidine-1-carboxylate (7b) (1.33 g, 2.27 mmol) was added at room temperature with hydrogen chloride (12 mL of 4M solution in dioxane, 48.00 mmol). Treated with. The reaction was then heated to 90 ° C. until LCMS indicated the reaction was complete. The mixture was concentrated to dryness and then vacuum dried to yield 1.04 g (88% yield) of compound (7c) as a tan solid.

LCMS RT = 2.3 min. ES ⁺ 487.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (methylsulfonyl) pyrrolidine-3- (1) Formation of Pyrimidin-4-amine (398)

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-N-[(3S)-in THF (1 mL) pyrrolidin-3-yl] pyrimidin-4-amine hydrochloride (7c) was added and _{^{i Pr 2 NEt (0.10㎖, 0.57mmol}} ) to a stirred suspension of (0.05g, 0.10mmol), methanesulfonyl chloride (0.04 mL, 0.57 mmol) was added. The homogeneous pale yellow mixture obtained was heated to 50 ° C. for 1 h, at which time LCMS showed a complete reaction. Morpholine (0.20 mL) was added and the solution was evaporated to dryness. The residue obtained was dissolved in methanol (2 mL), then treated with 25% sodium methoxide / methanol (0.5 mL) and heated to 60 ° C. in a closed tube until LCMS indicated the reaction was complete. The resulting solution was quenched with saturated aqueous NH ₄ Cl solution (0.5 mL) and then evaporated to dryness. The residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to give 15.8 mg (37% yield) of compound (398) as a solid.

LCMS RT = 1.7 min. ES ⁺ 411.

Other homologues which may be prepared in a similar manner to compound (398):

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (ethylsulfonyl) pyrrolidin-3-yl) -5- Formation of Fluoropyrimidin-4-amine (399)

21.7 mg (49% yield) of compound (399) were obtained using 50 mg (0.10 mmol) of compound (7c) and ethanesulfonyl chloride (54 μl, 0.57 mmol) according to the method for compound (398). .

LCMS RT = 1.8 min. ES ⁺ 425.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (isopropylsulfonyl) pyrrolidine-3 Formation of -yl) pyrimidin-4-amine (400)

2-Propansulfonyl chloride (82 mg, 0.57 mmol) was obtained according to the method for compound (398) to give 17.9 mg (39% yield) of compound (400) as a solid.

LCMS RT = 1.9 min. ES ⁺ 439.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopropylsulfonyl) pyrrolidin-3-yl) -5 Formation of Fluoropyrimidin-4-amine (401)

17.1 mg (yield 37%) of compound (401) was obtained using cyclopropanesulfonyl chloride (81 mg, 0.57 mmol) according to the method for compound (398).

LCMS RT = 1.9 min. ES ⁺ 437.

(S) -N- (1- (butylsulfonyl) pyrrolidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5- Formation of Fluoropyrimidin-4-amine 402

21-mg (45% yield) of compound 402 was obtained using 1-butanesulfonyl chloride (90 mg, 0.57 mmol) according to the method for compound 398.

LCMS RT = 2.1 min. ES ⁺ 453.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopentylsulfonyl) pyrrolidin-3-yl) -5 Formation of Fluoropyrimidin-4-amine (403)

Cyclopentanesulfonyl chloride (97 mg, 0.57 mmol) was obtained following the method for compound (398) to give 9.7 mg (yield 20%) of compound (403) as a solid.

LCMS RT = 2.1 min. ES ⁺ 465.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) pyrrolidine-3- (1) Formation of Pyrimidin-4-amine (410)

Propylsulfonyl chloride (20 mg, 0.14 mmol) was used to yield 15.5 mg (yield 36%) of solid (401) according to the method for compound (398).

LCMS RT = 2.0 min. ES ⁺ 439.

(S) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopentylmethylsulfonyl) pyrrolidin-3-yl)- Formation of 5-fluoropyrimidin-4-amine (479)

Cyclopentylmethyl sulfonyl chloride (30 mg, 0.16 mmol) was obtained according to the method for compound (398) to give 26.7 mg (Yield 58%) of compound (479) as a solid.

LCMS RT = 2.3 min. ES ⁺ 479.

(S) -methyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1 Formation of carboxylate 476

After preparative HPLC purification using methylchloroformate (20 mg, 0.21 mmol) according to the method for compound (398), 13.6 mg (yield 52%) of compound (476) were obtained as trifluoroacetic acid salt.

LCMS (ammonium formate buffer) RT = 2.6 min. ES ⁺ 391.

(S) -Isopropyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine- Formation of 1-carboxylate 477

After preparative HPLC purification using isopropyl chloroformate (20 mg, 0.21 mmol) according to the method for compound (476), 11.3 mg (yield 42%) of compound (477) were obtained as trifluoroacetic acid salt. .

LCMS (ammonium formate buffer) RT = 2.0 min. ES ⁺ 419.

(3S)-(tetrahydrofuran-3-yl) methyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 Formation of -ylamino) pyrrolidine-1-carboxylate (484)

Following preparative HPLC purification using 2,5-dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl) methyl carbonate (0.023 g, 0.096 mmol) according to the method for compound (398), the compound ( 484) 5.7 mg (yield 10%) were obtained as trifluoroacetic acid salt.

LCMS (ammonium formate buffer) RT = 2.6 min. ES ⁺ 461.

((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1 -Yl) (tetrahydrofuran-3-yl) methanone 478

Tetrahydrofuran-3-carboxylic acid (35 mg, 0.30 mmol) was obtained according to the method for compound 398 to give 22.2 mg (yield 52%) of compound (478) as a solid.

LCMS (TFA buffer) RT = 1.6 min. ES ⁺ 431.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine -1-yl) Formation of Ethanone 480

According to the method for compound (398), 4.2 mg (yield 18%) of compound (480) was obtained using acetyl chloride (45 mu l, 0.64 mmol).

LCMS (TFA buffer) RT = 1.6 min, ES ⁺ 375.

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine Formation of -1-yl) -2-methoxyethanone (481)

According to the method for compound (398) using methoxyacetyl chloride (50 mg, 0.46 mmol) to give 8.6 mg (33% yield) of compound (481) as a solid.

LCMS (TFA buffer) RT = 1.6 min, ES ⁺ 405.

(S)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1 -Yl) (3-methyloxetan-3-yl) methanone 482

17.7 mg (yield 42%) of compound (482) was obtained using 3-methyloxetane-3-carboxylic acid (15 mg, 0.13 mmol) according to the method for compound (398).

LCMS (TFA buffer) RT = 1.6 min, ES ⁺ 431.

((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1 -Yl) (morpholin-2-yl) methanone (483) formation

According to the method for compound (398), 3.6 mg (yield 8%) of compound (483) was obtained using morpholine 2-carboxylic acid (25 mg, 0.11 mmol).

LCMS (TFA buffer): Rt 1.4 min, ES ⁺ 446.

Other enantiomers 8a can be obtained using a process equivalent to that of compound 7c.

Homologs which can be prepared from compound (8a).

Scheme 8

(a) (S) -2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate, ⁱ Pr ₂ NEt, THF, RT (b) 25% NaOMe / MeOH or 1M LiOH, 150 ° C. , Microwave, 10 minutes.

(R)-((S) -tetrahydrofuran-3-yl) 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyripy Formation of midin-4-ylamino) pyrrolidine-1-carboxylate 424

(R) -tert-butyl 3-aminopyrrolidine-1-carboxylate and (S) -2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3 according to the method for compound (398) 19.8 mg (yield 47%) of compound (424) were obtained using -yl carbonate as a solid.

LCMS (TFA buffer) RT = 1.8 min, ES ⁺ 447.

(R)-(3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1 -Yl) (3-methyloxetan-3-yl) methanone (473)

(R) -2- (5-Chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- ( 18.6 mg (yield 44%) of compound (473) using pyrrolidin-3-yl) pyrimidin-4-amine hydrochloride (8a) and 3-methyloxetane-3-carboxylic acid (50 mg, 0.46 mmol) Was obtained as a solid.

LCMS (TFA buffer) RT = 1.6 min, ES ⁺ 431.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N- (1- (cyclopropylmethyl) pyrrolidin-3-yl) -5- Formation of Fluoropyrimidin-4-amine (415)

(S) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (pyrrolidine in methanol (3 mL) A solution of -3-yl) pyrimidin-4-amine hydrochloride (7c) (0.05 g, 0.10 mmol) was added to cyclopropane carboxaldehyde (0.30 mmol), sodium cyanoborohydride (0.30 mmol) and potassium acetate ( 0.04 g, 0.30 mmol) and then stirred at 60 ° C. until the reaction is complete. The oil was obtained by aqueous workup, which was dissolved in methanol (2 mL) and then treated with 25% sodium methoxide / methanol (0.5 mL) and heated to 60 ° C. in a closed tube. LCMS showed a complete reaction. The resulting solution was quenched with saturated aqueous NH ₄ Cl solution (0.5 mL), then evaporated to dryness, the residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to 6.2 mg (Yield 17). %) Was obtained as a solid.

LCMS RT = 1.5 min, ES ⁺ 387.

N- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -1- (methylsulfonyl) azepan- Formation of 4-amines (496)

Methanesulfonyl chloride was used following the method for compound 398 to afford the desired product 496 as a solid.

LCMS RT = 1.8 min, ES ⁺ 439.

1- (4- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azepan-1-yl) Formation of Ethanol 497

Acetyl chloride was used following the method for compound 398 to afford the desired product 497 as a solid.

LCMS RT = 1.7 min, ES ⁺ 403.

Methyl 4- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azepan-1-carboxylate (498 Formation of

Methyl chloroformate was used following the method for compound 398 to afford the desired product 498 as a solid.

LCMS RT = 1.9 min, ES ⁺ 419.

4- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N-dimethylazane-1 Formation of Carboxamide (499)

Dimethyl carbamoyl chloride was used according to the method for compound (398) to afford the desired colorant (499) as a solid.

LCMS RT = 1.8 min, ES ⁺ 432.

4- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azepan-1-carboxamide (509 Formation of

Trimethylsilylisocyanate was used following the method for compound 398 to afford the desired product 509 as a solid.

LCMS RT = 1.6 min, ES ⁺ 404.

4- (2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-methylazane-1-ka Formation of Voxamide 506

After treatment with HCl / dioxane using methyl isocyanate according to the method for compound 398, the desired product 506 was obtained as a hydrochloride salt.

LCMS RT = 2.1 min, ES ⁺ 418.

Scheme 11

(a) ⁱ Pr ₂ NEt, THF (b) 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) pyrrolo [2,3-b] pyridine, Pd (Ph ₃ P) ₄ , Na ₂ CO ₃ , DME, 130 ° C. (c) HCl / dioxane, CH ₂ Cl ₂ (d) 3- Methoxypropanoyl chloride, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ / DMF

Formation of (R) -tert-butyl 3-((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) -piperidine-1-carboxylate (11a)

2,4-dichloro-5-fluoropyrimidine (0.43 g, 2.59 mmol) and (R) -tert-butyl 3- (aminomethyl) piperidine-1-carboxylate (0.56) in THF (50 mL) g, 2.59 mmol) was added ⁱ Pr ₂ NEt (0.45 mL, 2.59 mmol). The reaction mixture was heated to 80 ° C. for 8 hours. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel chromatography (5-30% EtOAc / hexanes) to afford the desired product 11a.

LCMS (M + 1) 345.1.

(R) -tert-butyl 3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Formation of Piperidine-1-carboxylate (11b)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) blood in THF (30 mL) Rolo [2,3-b] pyridine (0.71 g, 1.65 mmol), (R) -tert-butyl 3-((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) -piperi -1-carboxylate (11a) (1.19g, 3.60mmol) and aqueous K ₂ CO ₃ (2M solution 2.48㎖, 4.97mmol) to a degassed solution of bis (tri-t-butylphosphine) palladium (0 ) (0.17 g, 0.33 mmol) was added. The reaction mixture was degassed for an additional 15 minutes. The mixture was stirred at rt for 4 h, concentrated in vacuo and the crude residue obtained was purified by silica gel chromatography (10% -80% EtOAc / hexanes) to afford the desired product (11b).

LCMS (M + 1) 461.4, (M-1) 460.7.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) pyrimidine-4 Formation of an amine (11c)

(R) -tert-butyl 3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in 5% MeOH / CH ₂ Cl ₂ To a solution of pyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (11b) (0.13 g, 2.8 mmol), 0.7 mL of 4N HCl / dioxane solution was added. The reaction mixture was stirred at rt for 12 h. The precipitate obtained was filtered off and used without further purification.

LCMS (M + 1) 361.1.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Formation of Piperidin-1-yl) -3-methoxypropan-1-one 327

2- (5-Chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro- in a 10: 1 mixture (1 mL) of CH ₂ Cl ₂ / DMF ^I Pr ₂ NEt (0.058 mL, 0.33 mmol) and 3-methoxypropanoyl in a solution of N- (piperidin-3-ylmethyl) pyrimidin-4-amine (11c) (0.04 g, 0.11 mmol) Chloride (0.02 g, 0.17 mmol) was added. After 12 hours, the solvent was concentrated in vacuo and the crude obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product 327.

LCMS (M + 1) 447.3.

Other homologues that may be prepared in the same manner as compound 327:

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-methoxyphenyl) methanone (113)

LCMS RT = 2.9 (M + 1) 479.4, (M-1) 477.6.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2- (thiophen-2-yl) ethanone (104)

LCMS RT = 2.8 (M + 1) 485.3, (M-1) 483.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3,5-difluorophenyl) methanone (108)

LCMS RT = 2.1 (M + 1) 501.3.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) ethanone (111)

LCMS RT = 2.5 (M + 1) 403.4.

(R) -benzo [b] thiophen-2-yl (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine -4-ylamino) methyl) piperidin-1-yl) methanone (107)

LCMS RT = 3.2 (M + 1) 521.3.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) ethanone (37)

LCMS RT = 2.5 (M + 1) 403.3.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (furan-2-yl) methanone (102)

LCMS RT = 2.7 (M + 1) 455.3, (M-1) 453.3.

(R) -2- (benzyloxy) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- 4-ylamino) methyl) piperidin-1-yl) ethanone (106)

LCMS RT = 3.0 (M + 1) 509.3, (M-1) 507.5.

(R) -2-fluoroethyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (126)

LCMS RT = 2.1 (M + 1) 451.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (thiophen-2-yl) methanone (97)

LCMS RT = 2.9 (M + 1) 471.2, (M-1) 469.6.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2,2-dimethylpropan-1-one (105)

LCMS RT = 3.0 (M + 1) 445.3, (M-1) 443.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,3-dimethylphenyl) methanone (157)

LCMS RT = 2.0 (M + 1) 493.1.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-phenoxyethanone (94)

LCMS RT = 2.9 (M + 1) 495.3, (M-1) 493.5.

(R) -2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-oxoethyl ethanoate (110)

LCMS RT = 2.5 (M + 1) 461.3, (M-1) 459.4.

(S) -ethyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carboxylate (33)

LCMS RT = 3.0 (M + 1) 433.3, (M-1) 431.4.

(R) -prop-1-en-2-yl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- 4-ylamino) methyl) piperidine-1-carboxylate (74)

LCMS RT = 3.1 (M + 1) 445.2, (M-1) 443.4.

(R) -3- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidine-1-carbonyl) pyrazine-2-carboxylic acid (82)

LCMS RT = 1.6 (M + 1) 511.3.

(1S, 2R) -2-((R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 -Ylamino) methyl) piperidine-1-carbonyl) cyclopropanecarboxylic acid (83)

LCMS RT = 1.6 (M + 1) 473.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-methoxyethanone (45)

LCMS RT = 2.4 (M + 1) 433.3, (M-1) 431.4.

(S) -allyl 3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carboxylate (17)

LCMS RT = 3.1 (M + 1) 445.3, (M-1) 443.4.

(R) -prop-2-ynyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino Methyl) piperidine-1-carboxylate (122)

LCMS RT = 2.9 (M + 1) 443.3, (M-1) 441.5.

(S) -ethyl 5- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl ) Piperidin-1-yl) -5-oxopentanoate (19)

LCMS RT = 2.8 (M + 1) 503.4, (M-1) 501.5.

(R) -but-2-ynyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (127)

LCMS RT = 3.1 (M + 1) 457.3, (M-1) 455.6.

(S) -methyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carboxylate (23)

LCMS RT = 2.8 (M + 1) 419.3, (M-1) 417.3.

(R) -allyl 3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1 -carboxylate (119)

LCMS RT = 3.1 (M + 1) 445.4, (M-1) 443.5.

(S) -but-2-ynyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (30)

LCMS RT = 3.1 (M + 1) 457.3, (M-1) 455.6.

(R) -tert-butyl 3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxylate (15)

LCMS RT = 2.7 (M + 1) 461.3.

(S) -isobutyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) py Ferridine-1-carboxylate (28)

LCMS RT = 3.3 (M + 1) 461.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) propan-1-one (32)

LCMS RT = 1.9 (M + 1) 417.2.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-methylpropan-1-one (34)

LCMS RT = 3.2 (M + 1) 447.4, (M-1) 445.5.

(S) -isopropyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) py Ferridine-1-carboxylate (35)

LCMS RT = 3.0 (M + 1) 447.3, (M-1) 445.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (cyclopentyl) methanone (99)

LCMS RT = 3.1 (M + 1) 457.3, (M-1) 455.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) but-2-en-1-one (41)

LCMS RT = 2.7 (M + 1) 429.3, (M-1) 427.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3,3-dimethylbutan-1-one (42)

LCMS RT = 3.1 (M + 1) 459.3, (M-1) 457.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3,3,3-trifluoropropan-1-one (44)

LCMS RT = 2.8 (M + 1) 471.3, (M-1) 469.4.

(S) -2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -N, N, N-trimethyl-2-oxoethanealuminum (43)

LCMS RT = 2.4 (M + 1) 460.3, (M-1) 458.5.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2- (dimethylamino) ethanone (46)

LCMS RT = 2.2 (M + 1) 446.4, (M-1) 444.5.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2- (pyridin-3-yl) ethanone (47)

LCMS RT = 2.4 (M + 1) 480.3, (M-1) 478.6.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) but-3-en-1-one (49)

LCMS RT = 2.7 (M + 1) 429.3, (M-1) 427.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethanone (48)

LCMS RT = 2.4 (M + 1) 471.3, (M-1) 469.4.

(R) -5-((S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidine-1-carbonyl) dihydrofuran-2 (3H) -one (51)

LCMS RT = 1.7 (M + 1) 472.9.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2- (1H-imidazol-1-yl) ethanone (50)

LCMS RT = 2.3 (M + 1) 469.3, (M-1) 467.4.

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) pent-4-yn-1-one (52)

LCMS RT = 1.9 (M + 1) 441.3.

(R) -5- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -5-oxopentanoic acid (53)

LCMS RT = 1.8 (M + 1) 475.3, (M-1) 473.4.

(R) -2- (2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino ) Methyl) piperidin-1-yl) -2-oxoethoxy) ethanoic acid (54)

LCMS RT = 1.7 (M + 1) 477.3, (M-1) 475.4.

(1S, 3R) -3-((R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 -Ylamino) methyl) piperidine-1-carbonyl) cyclopentanecarboxylic acid (55)

LCMS RT = 2.5 (M + 1) 501.3, (M-1) 499.6.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-fluorophenyl) methanone (58)

LCMS RT = 2.9 (M + 1) 483.3, (M-1) 481.5.

(R) -5- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3,3-dimethyl-5-oxopentanoic acid (80)

LCMS RT = 1.9 (M + 1) 503.3.

2-chloro-1-((R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidin-1-yl) propan-1-one (93)

LCMS RT = 2.9 (M + 1) 451.2, (M-1) 449.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (cyclohexyl) methanone (95)

LCMS RT = 3.2 (M + 1) 471.3, (M-1) 449.4.

(R) -tert-butyl 3-((2- (5-amino-1 H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxylate (114)

LCMS RT = 2.7 (M + 1) 461.3.

(R) -ethyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1-carboxyl Rate (495)

LCMS RT = 1.7 (M + 1) 385.4.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1 -Yl) -2-methoxyethanone (491)

LCMS RT = 1.7 (M + 1) 415.4.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1 -Yl) -3-methoxypropan-1-one (493)

LCMS RT = 1.7 (M + 1) 429.5.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1 -Yl) -3-methylbutan-1-one (494)

LCMS RT = 1.9 (M + 1) 427.5.

(S) -2-methoxyethyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (24)

LCMS RT = 2.8 (M + 1) 463.2, (M-1) 461.3.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-phenylethanone (56)

LCMS RT = 2.9 (M + 1) 479.3, (M-1) 477.4.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3-methylbut-2-en-1-one (57)

LCMS RT = 2.8 (M + 1) 443.3, (M-1) 441.4.

(R) -4- (methoxycarbonyl) phenyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 -Ylamino) methyl) piperidine-1-carboxylate (63)

LCMS RT = 3.2 (M + 1) 539.3, (M-1) 537.4.

(R) -phenyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carboxylate (68)

LCMS RT = 3.2 (M + 1) 481.4, (M-1) 479.4.

(R) -2-chlorophenyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxylate (70)

LCMS RT = 3.3 (M + 1) 515.3, (M-1) 513.3.

(R) -2-methoxyphenyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (69)

LCMS RT = 3.2 (M + 1) 511.3.

(R) -p-tolyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidine-1-carboxylate (71)

LCMS RT = 3.4 (M + 1) 495.3, (M-1) 493.4.

(R) -3- (trifluoromethyl) phenyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 -Ylamino) methyl) piperidine-1-carboxylate (72)

LCMS RT = 3.5 (M + 1) 549.3, (M-1) 547.4.

(R) -4-fluorophenyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (73)

LCMS RT = 3.3 (M + 1) 499.3, (M-1) 497.4.

(R) -2- (1- (2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 -Ylamino) methyl) piperidin-1-yl) -2-oxoethyl) cyclopentyl) ethanolic acid (81)

LCMS RT = 2.0 (M + 1) 529.3.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-chlorophenyl) methanone (84)

LCMS RT = 2.0 (M + 1) 499.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3,4-difluorophenyl) methanone (85)

LCMS RT = 2.1 (M + 1) 501.3.

(R) -2-chloro-1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidin-1-yl) ethanone (92)

LCMS RT = 2.7 (M + 1) 437.2, (M-1) 435.3.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,6-dichlorophenyl) methanone (96)

LCMS RT = 2.9 (M + 1) 535.2, (M-1) 533.2.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2- (4-fluorophenyl) ethanone (98)

LCMS RT = 2.9 (M + 1) 497.3, (M-1) 495.4.

(R) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-cyclopentylethanone (100)

LCMS RT = 3.1 (M + 1) 471.3, (M-1) 469.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (pyrazin-2-yl) methanone (111)

LCMS RT = 2.5 (M + 1) 467.2, (M-1) 465.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (furan-2-yl) methanone (186)

LCMS RT = 2.7 (M + 1) 455.3, (M-1) 453.3.

(R) -benzo [d] [1,3] dioxol-5-yl (3-((2- (5- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5 -Fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) methanone (103)

LCMS RT = 2.8 (M + 1) 509.3, (M-1) 507.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,4-difluorophenyl) methanone (152)

LCMS RT = 2.8 (M + 1) 501.3, (M-1) 499.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2- (methylamino) phenyl) methanone (112)

LCMS RT = 3.0 (M + 1) 494.3, (M-1) 492.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3,4-dimethoxyphenyl) methanone (109)

LCMS RT = 2.7 (M + 1) 525.3, (M-1) 523.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3,5-difluorophenyl) methanone (86)

LCMS RT = 2.8 (M + 1) 501, (M-1) 499.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (6-fluoro-4H-benzo [d] [1,3] dioxin-8-yl) methanone (142)

LCMS RT = 2.8 (M + 1) 541.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (o-tolyl) methanone (143)

LCMS RT = 2.9 (M + 1) 479.4, (M-1) 477.6.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2- (trifluoromethyl) phenyl) methanone (146)

LCMS RT = 3.0 (M + 1) 533.3, (M-1) 531.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,3-dihydrobenzofuran-6-yl) methanone (145)

LCMS RT = 2.9 (M + 1) 507.3, (M-1) 505.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,4-dichlorophenyl) methanone (147)

LCMS RT = 3.2 (M + 1) 533.3, (M-1) 531.4.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-ethoxyphenyl) methanone (158)

LCMS RT = 3.0 (M + 1) 509.4, (M-1) 507.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-methoxy-3-methylphenyl) methanone (148)

LCMS RT = 3.0 (M + 1) 509.3, (M-1) 507.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,5-difluorophenyl) methanone (151)

LCMS RT = 2.9 (M + 1) 501.2, (M-1) 499.5.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-phenoxyphenyl) methanone (150)

LCMS RT = 3.2 (M + 1) 557.3, (M-1) 555.6.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2,4-dimethoxyphenyl) methanone (154)

LCMS RT = 2.3 (M + 1) 525.3, (M-1) 523.2.

(R)-(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (cyclopropyl) methanone (325)

LCMS RT = 2.7 (M + 1) 429.2.

(R)-(3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1- Yl) (2-methoxyphenyl) methanone (272)

LCMS RT = 2.5 (M + 1) 461.3.

(R) -1- (3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine- Ethanone (268)

LCMS RT = 2.1 (M + 1) 369.3.

(R)-(3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1- Japanese) (phenyl) methanone (271)

LCMS RT = 2.5 (M + 1) 431.4.

(R) -1- (3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine- 1-day) butan-1-one (270)

LCMS RT = 2.4 (M + 1) 397.3.

(R)-(3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1- Yl) (phenyl) propan-1-one (269)

LCMS RT = 2.3 (M + 1) 383.3.

(S) -1- (3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine- 1-day) butan-1-one (225)

LCMS RT = 2.4 (M + 1) 397.4.

In a similar manner to the preparation of compound 327, compounds with opposite absolute stereochemistry were prepared as follows:

Scheme 12A

(a) tert-butylisocyanate, pyridine, CH ₂ Cl ₂

(S) -N-tert-butyl-3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) methyl) piperidine-1-carboxamide (20)

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in a mixture of pyridine / CH ₂ Cl ₂ (1 mL of 1: 1 mixture) To a solution of -N- (piperidin-3-ylmethyl) pyrimidin-4-amine (12a) (0.013 g, 0.036 mmol) was added tert-butyl isocyanate (0.005 mL, 0.046 mmol). The reaction mixture was stirred at 40 ° C. for 12 h. The solvent was concentrated under reduced pressure and the residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product (20).

LCMS RT = 3.0 (M + 1) 460.4, (M-1) 458.4.

Other homologues which may be prepared in the same manner as compound (20):

(R) -N-tert-butyl-3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidine-1-carboxamide (128)

LCMS RT = 3.0 (M + 1) 460.4, (M-1) 458.4.

(S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (Thiophen-3-yl) piperidine-1-carboxamide (22)

LCMS RT = 2.9 (M + 1) 486.3, (M-1) 484.6.

(S) -ethyl 2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxamido) ethanoate (25)

LCMS RT = 2.6 (M + 1) 490.3, (M-1) 488.4.

(S) -ethyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carbonylcarbamate (26)

LCMS RT = 2.5 (M + 1) 476.3, (M-1) 474.5.

(S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- Isopropylpiperidine-1-carboxamide (27)

LCMS RT = 2.7 (M + 1) 446.4, (M-1) 444.5.

(S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- Methylpiperidine-1-carboxamide (29)

LCMS RT = 2.4 (M + 1) 418.3, (M-1) 416.1.

(S) -N-allyl-3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxamide (39)

LCMS RT = 2.6 (M + 1) 444.4, (M-1) 442.4.

(S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (Pyridin-3-yl) piperidine-1-carboxamide (40)

LCMS RT = 2.5 (M + 1) 481.3, (M-1) 479.4.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3-fluorophenyl) piperidine-1-carboxamide (75)

LCMS RT = 3.0 (M + 1) 498.3, (M-1) 496.5.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide (76)

LCMS RT = 2.9 (M + 1) 510.3, (M-1) 508.5.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3-ethanoylphenyl) piperidine-1-carboxamide (77)

LCMS RT = 2.8 (M + 1) 522.3, (M-1) 520.4.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -Nm- Tolyl piperidine-1-carboxamide (78)

LCMS RT = 3.0 (M + 1) 494.3, (M-1) 492.4.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3- (trifluoromethyl) phenyl) piperidine-1-carboxamide (79)

LCMS RT = 3.3 (M + 1) 548.3, (M-1) 546.4.

(R) -ethyl 3- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxamido) propanoate (118)

LCMS RT = 2.6 (M + 1) 504.2, (M-1) 502.5.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (5-Methyl-2- (trifluoromethyl) furan-3-yl) piperidine-1-carboxamide (120)

LCMS RT = 3.2 (M + 1) 552.4, (M-1) 550.5.

(R) -methyl 2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxamido) ethanoate (125)

LCMS RT = 2.6 (M + 1) 490.4, (M-1) 488.6.

(R) -N-tert-butyl-3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidine-1-carboxamide (117)

LCMS RT = 2.8 (M + 1) 486.3, (M-1) 484.5.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (Thiophen-2-yl) piperidine-1-carboxamide (129)

LCMS RT = 2.8 (M + 1) 486.3, (M-1) 484.5.

(R) -methyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carbonylcarbamate (131)

LCMS RT = 1.6 (M + 1) 462.7.

(R) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (4-Methylthiophen-2-yl) piperidine-1-carboxamide (130)

LCMS RT = 2.0 (M + 1) 500.6.

(S) -3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N, N-dimethylpy Ferridine-1-carboxamide (228)

LCMS RT = 2.3 (M + 1) 398.3.

(R) -3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-methylpiperidine -1-Carboxamide (274)

LCMS RT = 2.1 (M + 1) 384.3.

(R) -N-ethyl-3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine -1-carboxamide (275)

LCMS RT = 2.2 (M + 1) 398.4.

(R) -3-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-propylpiperidine -1-Carboxamide (276)

LCMS RT = 2.3 (M + 1) 412.4.

Scheme 12B

(b) propyl isocyanate, ⁱ Pr ₂ NEt, pyridine, CH ₂ Cl ₂

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (methylsulfonyl) -piperidine- 3-yl) methyl) pyrimidin-4-amine (36)

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (piperidine- in CH ₂ Cl ₂ (0.7 mL) To a solution of 3-ylmethyl) pyrimidin-4-amine 12a (0.018 g, 0.050 mmol) and pyridine (0.7 mL) was added methanesulfonyl chloride (0.004 mL, 0.050 mmol). The reaction mixture was stirred at rt for 24 h. The solvent was concentrated under reduced pressure and the residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product (36).

LCMS RT = 2.7 (M + 1) 439.3, (M-1) 437.3.

Other homologues which may be prepared in the same manner as compound (36):

(R) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N-((1- (cyclopropylsulfonyl) piperidin-3-yl) methyl ) -5-fluoropyrimidin-4-amine (61)

LCMS RT = 2.8 (M + 1) 465.3, (M-1) 463.3.

(R, E) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (styrylsulfonyl) piperidine -3-yl) methyl) pyrimidin-4-amine (60)

LCMS RT = 3.2 (M + 1) 525.3.

(R) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (3-methoxyphenylsulfonyl) pi Ferridin-3-yl) methyl) pyrimidin-4-amine (62)

LCMS RT = 3.1 (M + 1) 531.3, (M-1) 529.4.

(R) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (4-fluorophenylsulfonyl) pi Ferridin-3-yl) methyl) pyrimidin-4-amine (64)

LCMS RT = 3.1 (M + 1) 519.3, (M-1) 517.4

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (3-fluorophenylsulfonyl) pi Ferridin-3-yl) methyl) pyrimidin-4-amine (65)

LCMS RT = 3.1 (M + 1) 519.2, (M-1) 517.4.

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (m-tolylsulfonyl) piperidine -3-yl) methyl) pyrimidin-4-amine (66)

LCMS RT = 3.2 (M + 1) 515.3, (M-1) 513.4

(R) -N-((1- (3-bromophenylsulfonyl) piperidin-3-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridine- 3-yl) -5-fluoropyrimidin-4-amine (67)

LCMS RT = 3.3 (M + 1) 579.2, (M-1) 577.2.

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (phenylsulfonyl) piperidine-3 -Yl) methyl) pyrimidin-4-amine (87)

LCMS RT = 2.1 (M + 1) 501.3.

(R) -N-((1- (3-bromophenylsulfonyl) piperidin-3-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridine- 3-yl) -5-fluoropyrimidin-4-amine (88)

LCMS RT = 2.0 (M + 1) 561.3.

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (phenylsulfonyl) piperidine-3 -Yl) methyl) pyrimidin-4-amine (89)

LCMS RT = 2.1 (M + 1) 507.2.

(R) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (2-fluorophenylsulfonyl) pi Ferridin-3-yl) methyl) pyrimidin-4-amine (90)

LCMS RT = 2.1 (M + 1) 519.2.

(R) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (1-methyl-1H-imidazole-) 4-ylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (91)

LCMS RT = 1.8 (M + 1) 505.3.

Scheme 12C

(a) (R) -3-bromo-2-methylpropan-1-ol, ⁱ Pr ₂ NEt, THF

(S) -3-((S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) methyl) piperidin-1-yl) -2-methylpropan-1-ol (135)

(R) -3-bromo-2-methylpropan-1-ol (0.006 mL, 0.055 mmol) and (R) -2- (5-chloro-lH-pyrrolo [2] in CH ₃ CN (2 mL). , 3-b] K in a solution of pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) -pyrimidin-4-amine (12a) (0.020 g, 0.055 mmol) ₂ CO ₃ (0.023 g, 0.165 mmol) was added. The reaction mixture was heated to 80 ° C. for 24 hours. The solvent was concentrated under reduced pressure and the residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product 135.

LCMS RT = 2.5 (M + 1) 433.4, (M-1) 431.6.

Other homologues that may be prepared in the same manner as compound 135:

(S) -1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3,3-dimethylbutan-2-one (140)

LCMS RT = 2.9 (M + 1) 459.3, (M-1) 457.5.

(R) -3-((S) -3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidin-1-yl) -2-methylpropan-1-ol (141)

LCMS RT = 1.4 (M + 1) 433.5.

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (2-methylbenzyl) piperidine- 3-yl) methyl) pyrimidin-4-amine (139)

LCMS RT = 3.2 (M + 1) 465.3, (M-1) 463.4.

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (3-methylbenzyl) piperidine- 3-yl) methyl) pyrimidin-4-amine (137)

LCMS RT = 3.1 (M + 1) 465.4, (M-1) 463.6.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N-((1- (cyclohexylmethyl) piperidin-3-yl) methyl) -5-fluoropyrimidin-4-amine (134)

LCMS RT = 3.1 (M + 1) 457.3, (M-1) 455.5.

(S) -2- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) ethanol (133)

LCMS RT = 2.3 (M + 1) 405.3, (M-1) 403.6.

(S) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N-((1- (2,2-dimethoxyethyl) piperidine-3- (L) methyl) -5-fluoropyrimidin-4-amine (132)

LCMS RT = 2.2 (M + 1) 449.7.

(S, E) -methyl 4- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino ) Methyl) piperidin-1-yl) but-2-enoate (138)

LCMS RT = 2.8 (M + 1) 459.3, (M-1) 457.7.

(S) -4- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) butanenitrile (666)

LCMS RT = 2.6 (M + 1) 428.3, (M-1) 426.5.

(S) -3- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) propanenitrile (667)

LCMS RT = 1.4 (M + 1) 414.5.

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (pyrimidin-2-yl) piperi Din-3-yl) methyl) pyrimidin-4-amine (124)

LCMS RT = 3.1 (M + 1) 439.3 (M-H) 437.4.

Scheme 13

(a) benzyl chloroformate, triethylamine, CH ₂ Cl ₂ ; (b) dimethyl sulfoxide, oxalyl chloride, triethylamine, CH ₂ Cl ₂ ; (c) DAST, THF; (d) 10% Pd / C, MeOH, H ₂ , di-tert-butyl dicarbonate (e) LiOH, THF / MeOH / water; (f) pyridine, di-tert-butyl dicarbonate, NH ₄ HCO ₃ , 1,4-dioxane; (g) triethylamine, TFAA, CH ₂ Cl ₂ ; (h) Raney Ni, MeOH, H ₂ ; (i) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, ⁱ Pr ₂ NEt, THF, microwave, 130 ° C. 15 minutes; (j) NaOMe, MeOH (k) isoproponal / HCl, 45 ° C .; (l) 3-methoxy propanoyl chloride, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ , DMF.

Formation of 1-benzyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (13b)

Cooled (5 ° C.) solution of methyl 4-hydroxypiperidine-2-carboxylate (13a) (5.17 g, 32.48 mmol) and triethylamine (6.00 mL, 43.05 mmol) in CH ₂ Cl ₂ (135 mL) Benzyl chloroformate (6.20 mL, 43.43 mmol) was added dropwise over 10 minutes. The resulting solution was stirred at 5 ° C. for 1 hour and then warmed to room temperature. The reaction mixture was diluted with water and the layers separated. The aqueous layer was extracted again with CH ₂ Cl ₂ and the combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The crude material was passed through a plug of silica gel eluting with 30-80% EtOAc / hexanes to give the desired product (13b).

Formation of 1-benzyl 2-methyl 4-oxopiperidine-1,2-dicarboxylate (13c)

To a flame dried 500 mL flask under N ₂ was added CH ₂ Cl ₂ (65 mL), followed by oxalyl chloride (5.2 mL, 59.6 mmol). The reaction mixture was cooled to −78 ° C., then dimethyl sulfoxide (8.4 mL, 118.4 mmol) was added, followed by 1-benzyl 2-methyl 4-hydroxypiperidine-1 in CH ₂ Cl ₂ (65 mL). , 2-dicarboxylate (13b) (8.6 g, 29.2 mmol) was added. The reaction was stirred at -78 ° C for 45 minutes. Triethylamine (24.4 mL, 175.1 mmol) was added to this mixture, and the mixture was warmed to room temperature. The reaction mixture was diluted with CH ₂ Cl ₂ and 1N HCl. The layers were separated and the aqueous phase was extracted again with CH ₂ Cl ₂ . The combined organic phases were washed with water, dried over MgSO ₄ , filtered and evaporated to dryness. The crude material was purified by silica gel chromatography (30-50% EtOAc / hexanes) to afford the desired product (13c).

Formation of 1-benzyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate (13d)

(Diethylamino) sulfur Trifluoride (25.0 mL, 189.2 mmol) was added. After 2 hours at 0 ° C., the reaction was quenched by careful addition of water. The mixture was diluted with EtOAc and water. The pH was adjusted to neutral by the addition of solid NaHCO ₃ . The layers were separated and the organic layer was washed with water and brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude material was passed through a plug of silica gel eluting with 15-20% EtOAc / hexanes to afford the desired product (13d).

Formation of 1-3-tert-butyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate (13e)

A Parr flask (1 L) was charged with 10% carbon supported palladium (0.57 g) and di-tert-butyl dicarbonate (4.47 g, 20.49 mmol). A solution of 1-benzyl 2-methyl-4,4-difluoropiperidine-1,2-dicarboxylate (13d) (4.28 g, 13.66 mmol) in methanol (150 mL) was added and the Parr shaker Hydrogen was introduced via (46 PSI). The reaction mixture was shaken at room temperature over the weekend. The mixture was filtered through Celite and washed well with CH ₂ Cl ₂ . The filtrate was concentrated to dryness and dissolved again in 10% EtOAc / hexanes. The crude material was purified by silica gel chromatography (10-20% EtOAc / hexanes) to give 5.1 g of a mixture of the desired product (13e) with approximately 840 mg of contaminated product. The crude mixture obtained was used directly in the next step without further purification.

Formation of 1- (tert-butoxycarbonyl) -4,4-difluoropiperidine-2-carboxylic acid (13f)

1-3-butyl 2-methyl 4,4-difluoropiperidine-1,2-dicarboxylate (13e) in THF (18 mL), methanol (18 mL) and H ₂ O (9 mL) To a solution of (4.6 g, 16.5 mmol) lithium hydroxide (3.45 g, 82.22 mmol) was added. The reaction mixture was stirred at rt for 1 h. All volatiles were removed at reduced pressure. The residue was diluted with a small amount of water and ether. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH 3 by addition of saturated aqueous KHSO ₄ solution. The product was extracted with EtOAc. The organic phase was washed with water, dried over MgSO ₄ , filtered and evaporated to dryness. The product obtained was used without further purification.

Formation of tert-butyl 2-carbamoyl-4,4-difluoropiperidine-1-carboxylate (13 g)

Pyridine in a solution of 1-3-butoxycarbonyl-4,4-difluoro-piperidine-2-carboxylic acid (13f) (1.67 g, 6.30 mmol) in 1,4-dioxane (12 mL) (0.35 mL, 4.33 mmol) was added followed by di-tert-butyl dicarbonate (1.78 g, 8.17 mmol) and ammonium bicarbonate (0.63 g, 7.86 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with water, saturated aqueous KHSO ₄ and brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude residue was used without further purification.

Formation of tert-butyl 2-cyano-4,4-difluoropiperidine-1-carboxylate (13h)

N, N to a solution of tert-butyl 2-carbamoyl-4,4-difluoro-piperidine-1-carboxylate (13 g) (1.72 g, 6.51 mmol) in CH ₂ Cl ₂ (50 mL) Triethylamine (2.03 mL, 14.61 mmol) was added followed by dropwise addition of (2,2,2-trifluoroacetyl) -2,2,2-trifluoroacetate (1.02 mL, 7.32 mmol). After 15 minutes, the mixture was diluted with saturated aqueous NaHCO ₃ solution and the layers separated. The organic phase was washed with water, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude residue was passed through a plug of silica gel and eluted with 10-30% EtOAc / hexanes to give the desired product (13h).

Formation of tert-butyl 2- (aminomethyl) -4,4-difluoropiperidine-1-carboxylate (13i)

Raney nickel (0.36 mL, 5.40 mmol) was washed with MeOH (twice) and charged to a Parr shaker. A solution of tert-butyl 2-cyano-4,4-difluoro-piperidine-1-carboxylate (13h) (1.33 g, 5.40 mmol) in methanol (50 mL) was added. The reaction mixture was treated under hydrogenation conditions overnight on a Parr shaker (46 PSI). The mixture was filtered through celite and washed well with CH ₂ Cl ₂ . All volatiles were removed at reduced pressure and the crude was used without further purification.

Tert-butyl 2-((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Formation of) -4,4-difluoropiperidine-1-carboxylate (13j)

Tert-butyl 2- (aminomethyl) -4,4-difluoro-piperidine-1-carboxylate (13i) (0.10 g, 0.41 mmol) and 5-chloro-3- in THF (2 mL) To a solution of (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (0.18 g, 0.38 mmol) ⁱ Pr ₂ NEt (0.20 mL, 1.15 mmol) was added. The reaction mixture was heated to 130 ° C. for 15 minutes in microwave. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc / hexanes) to afford the desired product (13j).

LCMS (M-1) 649.52.

Tert-butyl 2-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -4, Formation of 4-difluoropiperidine-1-carboxylate (13k)

Tert-butyl 2-[[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro in methanol (4 mL) Sodium methanolate (25% w) in a solution of rho-pyrimidin-4-yl] amino] methyl] -4,4-difluoro-piperidine-1-carboxylate (13j) (0.23 g, 0.35 mmol) / v 4 ml, 18.51 mmol) was added. The reaction mixture was stirred at rt for 15 min. All volatiles were removed at reduced pressure and the residue was quenched with water. EtOAc was added and the layers were separated. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and evaporated to dryness. The crude residue was pure enough for use without further purification.

LCMS (M + 1) 497.44, (M-1) 495.52.

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -N-((4,4-difluoropiperidin-2-yl) methyl) -5-fluor Formation of Ropyrimidin-4-amine (13m)

Tert-butyl 2-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4- in 2-propanol (2 mL) To a solution of monoamino) methyl) -4,4-difluoropiperidine-1-carboxylate (13k) (0.09 g, 0.18 mmol) was added propan-2-ol hydrochloride (6M 2 mL, 12.00 mmol). Added. The reaction mixture was stirred at rt for 17 h, then 1 ml of IPA / HCl was added and the reaction mixture was heated to 45 ° C. for 1 h. All volatiles were removed at reduced pressure and the residue was used directly in the next step without further purification.

LCMS (M + 1) 397.40, (M-1) 395.44.

1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -4,4 Formation of Difluoropiperidin-1-yl) -3-methoxypropan-1-one (584)

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl in CH ₂ Cl ₂ (1 mL), DMF (0.5 mL) and ⁱ Pr ₂ NEt (0.10 mL, 0.57 mmol). 3-methine in a solution of) -N-[(4,4-difluoro-2-piperidyl) methyl] -5-fluoro-pyrimidin-4-amine (13k) (0.086 g, 0.198 mmol) Toxypropanoyl chloride (2.43 g, 0.20 mmol) was added. The reaction mixture was stirred at rt for 17 h. All volatiles were removed at reduced pressure and the residue was purified via silica gel chromatography to give a mixture rich in the desired product (13) which was purified again via preparative HPLC.

Other homologues that may be prepared in the same manner as compound 584:

N-((4-benzylmorpholin-2-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 Amines (388)

2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-isopropylmorpholine 4-carboxamide (446)

LCMS RT = 1.7 (M + 1) 448.4

Isopropyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4- Carboxylate (447)

LCMS RT = 2.0 (M + 1) 449.3

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((4- (isopropylsulfonyl) morpholin-2-yl) methyl Pyrimidin-4-amine (448)

LCMS RT = 1.9 (M + 1) 469.3

1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) Propane-1-one (449)

LCMS RT = 1.7 (M + 1) 419.4

(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) (cyclo Methylone (450)

LCMS RT = 1.7 (M + 1) 431.4

Tert-butyl 3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine- 4-carboxylate (515)

1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) Propane-1-one (516)

LCMS RT = 1.9 (M + 1) 419.4

3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-propylmorpholine- 4-carboxamide (517)

Methyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxyl Rate (526)

LCMS RT = 2.4 (M + 1) 421.0.

Ethyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxyl Rate (527)

LCMS RT = 2.5 (M + 1) 435.1.

Allyl 3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxyl Rate (528)

LCMS RT = 2.6 (M + 1) 447.1.

1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) -2-methylpropan-1-one (529)

LCMS RT = 2.5 (M + 1) 433.1.

1- (3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) -2,2-dimethylpropan-1-one (530)

LCMS RT = 1.9 (M + 1) 447.1.

(3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) (cyclo Butyl) methanone (531)

LCMS RT = 2.6 (M + 1) 445.1.

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((4- (methylsulfonyl) morpholin-3-yl) methyl) Pyrimidin-4-amines (532)

LCMS RT = 2.4 (M + 1) 441.0.

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -N-((4- (cyclopropylsulfonyl) morpholin-3-yl) methyl) -5-fluor Ropyrimidin-4-amine (533)

LCMS RT = 2.4 (M + 1) 467.0.

3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carbox Amide (534)

LCMS RT = 2.0 (M + 1) 406.0.

3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-ethylmorpholine- 4-carboxamide (535)

LCMS RT = 2.2 (M + 1) 434.1.

3-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-isopropylmorpholine 4-carboxamide (536)

LCMS RT = 2.3 (M + 1) 448.1.

(R) -2-fluoroethyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (180)

LCMS RT = 2.1 (M + 1) 451.4.

(S) -2-methoxyethyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Methyl) piperidine-1-carboxylate (161)

LCMS RT = 2.8 (M + 1) 463.4.

(S) -2-chloroethyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl Piperidine-1-carboxylate (163)

LCMS RT = 3.1 (M + 1) 467.4.

(S) -prop-2-ynyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino Methyl) piperidine-1-carboxylate (164)

LCMS RT = 3.0 (M + 1) 443.5.

(S)-(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (thiazol-2-yl) methanone (165)

LCMS RT = 2.8 (M + 1) 472.5.

(S)-(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3-methoxyphenyl) methanone (174)

LCMS RT = 2.8 (M + 1) 495.6.

(S) -methyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1-carboxylate (166)

LCMS RT = 2.9 (M + 1) 419.5.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) ethanone (179)

LCMS RT = 2.5 (M + 1) 403.4.

(S) -ethyl 2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Dean-1 -carboxylate (171)

LCMS RT = 3.0 (M + 1) 433.3.

(R)-(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3-methoxyphenyl) methanone (184)

LCMS RT = 2.7 (M + 1) 495.5.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) propan-1-one (208)

LCMS RT = 1.9 (M + 1) 417.2.

(R)-(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (2-methoxyphenyl) methanone (190)

LCMS RT = 2.9 (M + 1) 495.4.

(R)-(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (4-fluorophenyl) methanone (209)

LCMS RT = 2.0 (M + 1) 483.1.

(R)-(2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperi Din-1-yl) (3- (trifluoromethyl) phenyl) methanone (210)

LCMS RT = 2.2 (M + 1) 533.1.

(R) -4-chloro-1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) methyl) piperidin-1-yl) butan-1-one (278)

LCMS RT = 2.4 (M + 1) 465.1.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) pent-4-en-1-one (279)

LCMS RT = 2.1 (M + 1) 443.2.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3,3,3-trifluoropropan-1-one (280)

LCMS RT = 2.1 (M + 1) 471.2.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) hex-5-yn-1-one (281)

LCMS (M + 1) 454.2.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -3-phenylpropan-1-one (293)

LCMS RT = 3.1 (M + 1) 493.2.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) -2-cyclohexylethanone (294)

LCMS RT = 3.3 (M + 1) 485.2.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) butan-1-one (295)

LCMS RT = 2.9 (M + 1) 431.2.

(R) -1- (2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) Piperidin-1-yl) pentan-1-one (326)

LCMS RT = 3.0 (M + 1) 445.2.

(S) -1- (2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine- 1-day) ethanone (256)

LCMS RT = 2.2 (M + 1) 369.3.

(S) -1- (2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine- 1-yl) propane-1-one (257)

LCMS RT = 2.3 (M + 1) 383.3.

(S) -1- (2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine- 1-day) butan-1-one (258)

LCMS RT = 2.5 (M + 1) 397.3.

(S)-(2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1- Day) (phenyl) methanone (259)

LCMS RT = 2.4 (M + 1) 431.3.

(S)-(2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1- Yl) (2-methoxyphenyl) methanone (260)

LCMS RT = 2.4 (M + 1) 461.3.

(R) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (methylsulfonyl) -piperidine- 2-yl) methyl) pyrimidin-4-amine (381)

LCMS RT = 2.7 min, (M + H) 439.3

(R) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (ethylsulfonyl) -piperidine- 2-yl) methyl) pyrimidin-4-amine (382)

LCMS RT = 2.9 min, (M + H) 453.3.

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (propylsulfonyl) piperidine-2 -Yl) methyl) pyrimidin-4-amine (328)

LCMS RT = 2.2 min, (M + H) 467.1.

(R) -2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (2,2,2-trifluoro) -Ethylsulfonyl) -piperidin-2-yl) methyl) pyrimidin-4-amine (383)

LCMS RT = 3.0 min, (M + H) 507.3.

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (methylsulfonyl) -piperidine- 2-yl) methyl) pyrimidin-4-amine (384)

LCMS RT = 2.7 min, (M + H) 439.3.

(R) -N-((1- (butylsulfonyl) piperidin-2-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine (329)

LCMS RT = 2.3 min, (M + H) 481.2.

(S) -2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1- (cyclopropylsulfonyl) -piperidine -2-yl) methyl) pyrimidin-4-amine (386)

LCMS RT = 2.9 min, (M + H) 465.3.

(R) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -N-((1- (3-chloropropylsulfonyl) piperidin-2-yl Methyl) -5-fluoropyrimidin-4-amine (330)

LCMS RT = 2.2 min, (M + H) 501.1.

(R) -2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-isopropylpiperi Dean-1-carboxamide (371)

LCMS RT = 1.8 min, (M + H) 412.2.

(R) -N-cyclopropyl-2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) -methyl) py Ferridine-1-carboxamide (372)

LCMS RT = 1.9 min, (M + H) 424.2.

(R) -N-ethyl-2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) -methyl) piperi Dean-1-carboxamide (373)

LCMS RT = 1.7 min, (M + H) 398.2.

(R) -2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-methylpiperidine -1-Carboxamide (374)

LCMS RT = 1.6 min, (M + H) 384.2.

(R) -2-((5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-propylpiperidine -1-Carboxamide (375)

LCMS RT = 1.8 min, (M + H) 412.2.

Scheme 14

(a) ⁱ Pr ₂ NEt, isopropanol, 80 ° C. (b) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 -Tosyl-1H-pyrrolo [2,3-b] pyridine, Pd (Ph ₃ P) ₄ , Na ₂ CO ₃ , DME, 130 ° C. (c) HCl / dioxane, CH ₂ Cl ₂ (d) propyl isocyanate , Pyridine, CH ₂ Cl ₂

Formation of 1-((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol (14a)

^I Pr in a solution of 2- (aminomethyl) cyclohexanol hydrochloride (0.09 g, 0.54 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.10 g, 0.60 mmol) in isopropanol (2 mL) ₂ NEt (0.21 mL, 1.20 mmol) was added. The reaction mixture was heated to 80 ° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel chromatography (25% -75% EtOAc / hexanes) to afford the desired product 14a.

LCMS (M + 1) 260.1, (M-1) 258.3.

2-((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol Formation of 14b

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo in dimethylacetamide [ 2,3-b] pyridine (0.15 g, 0.35 mmol), 1-((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol (14a) (0.09 g, 0.35 mmol) And palladium triphenylphosphine (0.04 g, 0.03 mmol) was added to the degassed solution of KOAc aqueous solution (1.04 mL of 1 M solution, 1.04 mmol). The reaction mixture was heated to 140 ° C. for 15 minutes in microwave and then cooled to room temperature. The reaction mixture was filtered through celite, concentrated in vacuo and the crude residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product (14b).

LCMS RT = 2.6 (M + 1) 530.3.

(2R) -2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol Formation of 12

2-((2- (5- (1-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino in THF (3 mL)) To a solution of) methyl) cyclohexanol (14b) (0.10 g, 0.19 mmol) was added aqueous lithium hydroxide (1 mL of 1N solution). The reaction mixture was stirred at rt for 12 h. The residue obtained was purified by preparative HPLC (0.1% TFA-H ₂ O / acetonitrile) to afford the desired product (12).

LCMS FIA RT = 1.9 (M + 1) 376.2.

2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol (13)

LCMS FIA RT = 1.8 (M + 1) 362.2.

2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanol (14)

LCMS FIA RT = 1.0 (M + 1) 348.3.

(1R, 2S, 3R, 5R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -5- (hydroxymethyl) cyclopentane-1, 2-diol (657)

Scheme 14B

(a) Raney-Ni, H ₂ (50 PSI), EtOH (b) 15a, THF, 70 ° C (c) TFA, CH ₂ Cl ₂ (d) 1N LiOH, THF, 120 ° C

Formation of tert-butyl trans-2- (aminomethyl) cyclohexylcarbamate (14d)

A solution of tert-butyl trans-2-cyanocyclohexylcarbamate and Raney-Ni in anhydrous EtOH was stirred for 24 h under H ₂ atmosphere (50 PSI). After filtration and evaporation of the solvent, the target compound (14d) was obtained as a racemic mixture of trans isomers by flash chromatography (SiO ₂ , 0-20% MeOH-CH ₂ Cl ₂ , gradient elution) (286 mg, Yield 66%).

FIA (M + H) 229.33.

Tert-butyl trans-2-((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl -Amino) methyl) cyclohexylcarbamate (14e)

5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (15a) (0.42 g, 0.90 mmol) and tert-butyl trans-2- (aminomethyl) cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated to 70 ° C. in THF (10 mL). After 1.3 h, the mixture was concentrated in vacuo. Flash chromatography (SiO ₂ , 0-60% EA / Hex, gradient elution) to the desired intermediate, tert-butyl trans-2-((2- (5-chloro-1-tosyl-1H-pyrrolo [2 , 3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexylcarbamate (14e) was obtained as a racemic mixture of trans isomers, which was subsequently obtained without further purification. Used for reaction (0.52 g, 92% yield).

N-((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine Formation of 4-amine (14f)

Tert-butyl trans-2-((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5- in CH ₂ Cl ₂ (5 mL) A solution of fluoropyrimidin-4-ylamino) methyl) cyclohexylcarbamate (14e) (0.52 g) was treated with TFA (2.5 mL) for 30 minutes. The solution was concentrated in vacuo and the crude obtained was taken up in CH ₃ CN and concentrated in vacuo several times to remove excess TFA and the desired amine (14f) as a racemic mixture of trans isomers as a TFA salt, which was subsequently Pure enough for use in the reaction.

LCMS RT = 1.93 min, (M + H) 529.0

N-((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine Formation of 555

N-((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in THF A solution of pyrimidin-4-amine (14f) (0.050 g, 0.077 mmol) was treated with LiOH (0.5 mL, 1.0 M) at 60 ° C. After 5 minutes, at 120 ° C., the solution was diluted with EtOAc, washed with brine, filtered and concentrated in vacuo. Preparative HPLC gave the desired compound (555) as a racemic mixture of trans isomers (12 mg, yield 33%).

Scheme 14C

(a) i: RCOCl, DIEA, CH ₂ Cl ₂ ii: 1N LiOH, THF, 120 ° C.

N- (trans-2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexyl ) -2-methoxyethaneamide (556)

N-((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridine in CH ₂ Cl ₂ (2 mL) at 0 ° C. 3-methoxyacetyl chloride (0.010 g, in a cooled mixture of -3-yl) -5-fluoropyrimidin-4-amine (0.060 g, 0.093 mmol) and ⁱ Pr ₂ NEt (0.057 mL, 0.330 mmol) 0.098 mmol) was added. After 5 minutes, the solution was allowed to warm to room temperature. After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1 mL) and treated with LiOH (0.326 mL, 1.0 M solution) at 120 ° C. for 10 min. The resulting mixture was cooled to rt, partitioned, the aqueous layer was extracted with EtOAc and the combined organic layers were concentrated in vacuo. Preparative HPLC gave the desired product 556 as a racemic mixture of TFA salts (8.6 mg, yield 17%).

The following homologues can be prepared in the same manner as compound 556.

N- (trans-2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexyl Formation of Methanesulfonamide (557)

Sulfonamide (557) was prepared according to the process for Scheme 36 (Scheme 12B) with N-((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [ Prepared by obtaining the desired product (557) as a racemic mixture of trans isomers using 2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine (14f) and methane sulfonyl chloride. It became.

3- (trans-2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexyl Formation of) -1,1-dimethylurea 564

Urea 564 was prepared according to the process for Scheme 20 (Scheme 12A) N-((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2 , 3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine (14f) and dimethylcarbomoyl chloride to give the desired product 564 as racemic mixture of trans isomers. .

Scheme 15

(a) (1S, 2S) -cyclohexane-1,2-diamine, THF, 140 ° C. (b) AcCl, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ (c) 1M LiOH, DCE, 150 ° C., microwave 20 minute.

(1S, 2S) -N1- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclo Formation of Hexane-1,2-diamine (15b)

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (15a) (0.25 g, 0.53 mmol) and (1S, 2S) -cyclohexane-1,2-diamine (0.12 g, 1.08 mmol) were dissolved in THF (3.0 mL) and heated to 140 ° C. for 20 minutes in a closed vial. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (0% -15% MeOH / CH ₂ Cl ₂ ) to give the product (15b) as a white foamy solid (220 mg, 79% yield). .

N-[(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Formation of amino] cyclohexyl] acetamide (433)

(1S, 2S) -N- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-pyrimidine-4 -Yl] cyclohexane-1,2-diamine (15b) (0.100 g, 0.194 mmol) was dissolved in dichloromethane (2 mL) and treated with ⁱ Pr ₂ NEt (0.075 g, 0.101 mL, 0.583 mmol). Acetyl chloride (0.021 mL, 0.291 mmol) was added and the reaction stirred for 30 minutes at room temperature. The volatiles were evaporated under reduced pressure, the residue was dissolved in dichloroethane (2 mL) and treated with LiOH (0.097 mL, 0.971 mmol) of 1M solution. The reaction mixture was heated to 150 ° C. for 10 minutes in microwave. The reaction was diluted with EtOAc (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2 × 5 mL) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was silica gel chromatography (0% -15% MeOH / CH ₂ Cl _2). Purified by N-[(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidine -4-yl] amino] cyclohexyl] acetamide (433) (34 mg, yield 44%) was provided.

Scheme 16

(a) cyclohexane-cis-1,2-diamine, isopropanol, ⁱ Pr ₂ NEt (b) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Il) -1H-pyrrolo [2,3-b] pyridine, Pd (PPh ₃ ) ₄ , Na ₂ CO ₃ , DME: DCE, 150 ° C., microwave; (c) 1M LiOH 150 ° C., microwave; (d) MeSO ₂ Cl, ⁱ Pr ₂ NEt, DMF: DCM.

Formation of N1- (2-chloro-5-fluoropyrimidin-4-yl) cyclohexane-cis-1,2-diamine (16a)

2,4-Dichloro-5-fluoropyrimidine (0.50 g, 2.99 mmol) was dissolved in isopropanol (7 mL) and treated with ⁱ Pr ₂ NEt (1.50 mL, 8.98 mmol). Cyclohexane-cis-1,2-diamine (0.46 g, 4.03 mmol) was added and the reaction was stirred at rt overnight. The solvent was evaporated and the reaction mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product. The obtained crude material was purified by silica gel chromatography (5% -30% MeOH / CH ₂ Cl ₂ ) to give compound 16a (370 mg, 50% Soul) as a white solid.

Formation of N1- (5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1,2-diamine (16b)

3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine (0.26 g, 0.65 mmol) Dissolved in DME (8 mL) and treated with N1- (2-chloro-5-fluoropyrimidin-4-yl) cyclohexane-cis-1,2-diamine (16a) (0.16 g, 0.65 mmol). . Pd (PPh ₃ ) ₄ (0.10 mg, 0.08 mmol) and 2M aqueous Na ₂ CO ₃ (3.25 mL) were added and the suspension was heated to 150 ° C. for 20 minutes in microwave. 1M aqueous LiOH (5 mL) was added and the reaction was heated to 150 ° C. for 15 minutes in a microwave. The organic solvent was evaporated under reduced pressure and the aqueous phase extracted with CH ₂ Cl ₂ ( ₂ × ₂₀ mL). The combined organic phases were dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue obtained was purified by silica gel chromatography (0% -100% CH ₂ Cl ₂ / EtOAc) to give product 16b (140 mg, yield 66%) as a brown foam.

N- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] methanesulfonamide ( 337) Formation

N1- (5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1,2-diamine (16b) (0.009 g, 0.027 mmol) was dissolved in an 8: 2 mixture of CH ₂ Cl ₂ / DMF (1 mL) and treated with ⁱ Pr ₂ NEt (0.019 mL, 0.110 mmol) and methanesulfonyl chloride (0.006 mL, 0.083 mmol). The reaction was stirred at rt overnight, concentrated in vacuo and the residue was purified by HPLC (10% -90% acetonitrile / water + 0.03% TFA) to give compound 337.

The following compounds can be prepared in a manner similar to that described in either Scheme 15 or Scheme 16:

N- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] -cyclohexyl] propanamide ( 341)

N- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] butanamide (342 )

LCMS RT = 2.5 (M + 1) 397.4.

N- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] cyclopentanecarbox Amide (343)

LCMS RT = 2.7 (M + 1) 423.4.

N- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] benzamide (344 )

LCMS RT = 2.7 (M + 1) 431.4.

N- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] propane-1- Sulfonamide (346)

1- [cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] -3-propyl Urea (347)

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Acetamide (348)

N- [trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] Propanamide (349)

LCMS RT = 2.7 (M + 1) 417.3.

N-[(1R, 2R) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] cyclopentanecarboxamide (351)

LCMS RT = 3.1 (M + 1) 457.3.

N-[(1R, 2R) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] benzamide (352)

LCMS RT = 3.0 (M + 1) 465.3.

N-[(1R, 2R) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] methanesulfonamide (353)

LCMS RT = 2.7 (M + 1) 439.4.

N-[(1R, 2R) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] propane-1-sulfonamide (354)

LCMS RT = 3.0 (M + 1) 467.3.

1-[(1R, 2R) -2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -3-propyl-urea (355)

LCMS RT = 2.8 (M + 1) 446.3.

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Butanamide (358)

LCMS RT = 2.5 (M + 1) 397.4.

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Cyclopentanecarboxamide (359)

LCMS RT = 2.7 (M + 1) 423.4.

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Benzamide (360)

LCMS RT = 2.63 (M + 1) 431.4.

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Methanesulfonamide (361)

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Propane-1-sulfonamide (362)

N- [trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Butanamide (363)

LCMS RT = 2.9 (M + 1) 431.3.

N-[(trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclo Hexyl] cyclopentanecarboxamide (364)

LCMS RT = 3.1 (M + 1) 457.3.

N- [trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Benzamide (365)

LCMS RT = 3.0 (M + 1) 465.3.

N- [trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Propane-1-sulfonamide (367)

LCMS RT = 3.0 (M + 1) 467.3.

1- [trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -3-propyl-urea (368)

LCMS RT = 2.8 (M + 1) 446.3.

Methyl N-[(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] Amino] cyclohexyl] carbamate (425)

1-[(1S, 2S) -2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -3-methyl-urea (426)

3-[(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -1,1-dimethyl-urea (427)

N-[(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] methanesulfonamide (428)

1- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -3-methyl-urea (430)

3- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -1,1-dimethyl-urea (431)

Methyl N- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclo Hexyl] carbamate (432)

N- [5-fluoro-2- (1H-pyrrolo [5,4-b] pyridin-3-yl) pyrimidin-4-yl] cyclohexane-cis-1,2-diamine (206)

LCMS RT = 1.9 (M + 1) 327.2.

Trans-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexanol (207)

LCMS RT = 2.2 (M + 1) 328.2.

Cis-2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexanol (277)

LCMS RT = 1.6 (M + 1) 328.2.

N- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] Propanamide (333)

LCMS RT = 2.7 (M + 1) 417.4.

N- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Butanamide (334)

LCMS RT = 2.9 (M + 1) 431.4.

N- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] Cyclopentanecarboxamide (335)

LCMS RT = 3.1 (M + 1) 457.3.

N- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Benzamide (336)

LCMS RT = 3.0 (M + 1) 465.4.

N- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Propane-1-sulfonamide (338)

LCMS RT = 2.9 (M + 1) 467.3.

1- [cis-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -3-propyl-urea (339)

LCMS RT = 2.9 (M + 1) 446.3.

1- [trans-2-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -3-propyl-urea (350)

LCMS RT = 2.6 (M + 1) 403.3.

N-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] Propanamide (356)

LCMS RT = 2.3 (M + 1) 383.4.

(1R, 2R) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5- (trifluoromethyl) pyrimidin-4-yl) cyclo Hexane-1,2-diamine (31)

LCMS RT = 2.2 (M + 1) 411.2.

N1- (5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1,2-diamine (4)

LCMS RT = 2.2 (M + 1) 327.2.

(1R, 2R) -N1- (5-chloro-2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1,2 -Diamine (115)

LCMS RT = 1.3 (M + 1) 377.2.

N1- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methylpyrimidin-4-yl) cyclohexane-1,2-diamine (116)

LCMS RT = 3.3 (M + 1) 357.2.

N-[(1R, 2R) -2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] butanamide (369)

LCMS RT = 2.9 (M + 1) 431.3.

1-[(1R, 2R) -2-[[5-fluoro-2- (1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] 3-propyl-urea (370)

LCMS RT = 2.4 (M + 1) 412.4.

2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- (2-methoxycyclohexyl) -pyrimidin-4-amine (412)

LCMS RT = 3.5 (M + 1) 376.4.

Scheme 18

i. DPPA, Et ₃ N, toluene, 110 ° C .; ii BnOH, 85 ° C. (b) LiOH, THF: H ₂ O (c) Boc ₂ O, pyridine, NH ₄ HCO ₃ , dioxane (d) BTIB, CH ₃ CN: H ₂ O.

Formation of (1S, 3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid (18a)

(1S, 3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid is described in Barnett, CJ, Gu, RL, Kobierski, ME, WO-2002024705, Stereoselective process for preparing cyclohexyl amine derivatives. It can be prepared according to the.

Formation of ethyl (1R, 3S) -3-benzyloxycarbonylaminocyclohexanecarboxylate (18b)

(1S, 3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid (18a) (10.0 g, 49.9 mmol) was dissolved in toluene (100 mL), triethylamine (7.6 mL, 54.9 mmol) and DPPA ( 12.2 mL, 54.9 mmol). The resulting solution was heated to 110 ° C. and stirred for 1 hour. After cooling to 70 ° C., benzyl alcohol (7.7 mL, 74.9 mmol) was added and the mixture was heated to 85 ° C. overnight. The resulting solution was cooled to rt, poured into EtOAc (150 mL) and water (150 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2x75 mL) and the combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude material was purified by silica gel chromatography (0% -50% EtOAc / hexanes) to afford compound 18b (15.3 g, containing ˜25% benzyl alcohol), which was used in the next step without further purification. .

Formation of (1R, 3S) -3-benzyloxycarbonylaminocyclohexanecarboxylic acid (18c)

Ethyl (1R, 3S) -3-benzyloxycarbonylaminocyclohexanecarboxylate (18b) (36 g, 117.9 mmol) was dissolved in THF (144.0 mL) and LiOH (5.647 g, 235.8 mmol) in water (216.0 mL). ) Solution. After stirring overnight, the reaction mixture was diluted with water (100 mL), washed with methyl tert-butyl ether (150 mL) and 3N HCl was added to pH 3. The acidic solution is extracted with EtOAc (3x100 mL), the combined organic layers are washed with water and brine, dried over Na ₂ S0 ₄ , Concentrated in vacuo.

The crude product was triturated with methyl tert-butyl ether (30 mL) and filtered to give a first crystal harvest. The filtrate was treated with heptane (20 mL), concentrated to 30 mL and left at room temperature for 3 hours to give a second crystal harvest which was recovered by filtration to give a total of 14.4 g (44% yield) of compound (18c). ) Was obtained.

Formation of benzyl N-[(1S, 3R) -3-carbamoylcyclohexyl] carbamate (18d)

Pyridine (2.9 mL, 36.1 mmol) was added to a solution of (1R, 3S) -3-benzyloxycarbonylaminocyclohexanecarboxylic acid (18c) (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL). Then, di-tert-butyl dicarbonate (10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol) were added. After 3 hours, another fraction of di-tert-butyl dicarbonate (1.5 g, 6.8 mmol) and ammonium bicarbonate (1.5 g, 6.8 mmol) were added again and stirring continued overnight. The reaction was quenched by addition of 2N HCl (400 mL) and stirred for 1 hour. The resulting suspension was filtered under reduced pressure, washed with 2N HCl (50 mL), water (8x50 mL) and hexanes (3x50 mL), and dried in vacuo to benzyl N-[(1S, 3R) -3-carbamoylcyclohexyl] Carbamate 18d (9.1 g, 91%) was provided as a white solid.

Formation of benzyl N-[(1S, 3R) -3-aminocyclohexyl] carbamate (18e)

Benzyl N-[(1S, 3R) -3-carbamoylcyclohexyl] carbamate (18d) (9.1 g, 32.9 mmol) was suspended in a mixture of acetonitrile (100 mL) and water (100 mL) and bis ( Trifluoroacetoxy) iodobenzene (15.5 g, 36.1 mmol). The suspension was stirred overnight at room temperature and then quenched with 1N HCl (100 mL). After evaporating acetonitrile, the acidic aqueous solution was washed with EtOAc (2x150 mL). The pH was adjusted to basic by the addition of solid KOH and the obtained emulsion was extracted with EtOAc (3x200 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give product 18e (6.2 g, yield 75%).

Scheme 19

(a) MeOCOCl, Et ₃ N, THF (b) H ₂ , Pd / C, EtOH (c) 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)- 1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine, THF, 130 ° C., microwave (d) LiOH, 130 ° C., microwave.

Formation of Methyl N-[(1R, 3S) -3-benzyloxycarbonyl-aminocyclohexyl] carbamate (19a)

Benzyl N-[(1S, 3R) -3-aminocyclohexyl] carbamate (18e) (0.99 g, 3.99 mmol) was dissolved in THF (20 mL) and diluted with methyl chloroformate (0.62 mL, 7.97 mmol). After treatment, it was treated with triethylamine (1.67 mL, 11.96 mmol). After stirring for 1 hour at room temperature, the solvent is evaporated under reduced pressure, and the residue is diluted with a 1: 3 mixture of CH ₂ Cl ₂ : EtOAc (130 mL), 1N HCl (50 mL) and 2N Na ₂ CO ₃ (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford the desired product 19a as a white solid (1.09 g, 89% yield).

Formation of Methyl N-[(1R, 3S) -3-aminocyclohexyl] carbamate (19b)

Methyl N-[(1R, 3S) -3-benzyloxycarbonylaminocyclohexyl] carbamate (19a) (1.09 g, 3.56 mmol) was dissolved in ethanol (100 mL) and 10% Pd / C (0.38 g) , 0.36 mmol). The flask was capped, degassed, a hydrogen balloon installed and stirred overnight. The reaction mixture was filtered under nitrogen and concentrated in vacuo to give the product 19b as a white solid.

Methyl N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] Amino] cyclohexyl] carbamate (570)

5-Chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) -pyrrolo [2,3-b] pyridine (19b) ( 2.04 g, 4.39 mmol) and methyl N-[(1R, 3S) -3-amino-cyclohexyl] carbamate (0.60 g, 3.14 mmol) were suspended in THF (16 mL) and 130 ° C. in a microwave for 20 minutes. Heated to. Lithium hydroxide (15.67 mL of 1M solution, 15.67 mmol) was added and the resulting mixture was heated to 130 ° C. for 20 minutes in a microwave. The resulting solution was diluted with water (150 mL) and ethyl acetate (200 mL) and the layers separated. The aqueous layer was extracted with EtOAc (100 mL), the organic layers combined, dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% EtOAc / hexanes) and then pure fractions were treated with 4N HCl in dioxane to give the hydrochloride of compound 570 as off-white solid.

Scheme 20

(a) 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine, THF (b) CH ₂ Cl ₂ , trifluoroacetic acid (c) acetyl chloride, Et ₃ N, THF (d) LiOH, 130 ° C., microwave.

Tert-butyl N-[(1R, 3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5 -Fluoro-pyrimidin-4-yl] amino] cyclohexyl] carbamate (20b)

Tert-butyl N-[(1R, 3S) -3-aminocyclohexyl] carbamate (20a) (0.15 g, 0.70 mmol) and 5-chloro-3- (5-fluoro-4-methylsulfinyl- Pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (1a) (0.49 g, 1.05 mmol) is dissolved in THF (30 mL) and overnight at room temperature Stirred. The solvent was evaporated under reduced pressure and the residue was purified by two silica gel chromatography-first (0% -10% MeOH / CH ₂ Cl ₂ ), second (10% -50% EtOAc / hexanes) Tert-butyl N-[(1R, 3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5 -Fluoro-pyrimidin-4-yl] amino] cyclohexyl] carbamate (20b) (330 mg, 38%) was provided.

(1R, 3S) -N1- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4 -Yl] cyclohexane-1,3-diamine (20c) formation

Tert-butyl N-[(1S, 3R) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5 -Fluoro-pyrimidin-4-yl] amino] cyclohexyl] carbamate (20b) (0.33 g, 0.53 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and trifluoroacetic acid (2 mL). Treated. After stirring for 2 hours, the solvent is evaporated under reduced pressure and the residue obtained is passed through a polymer supported carbonate column to give (1R, 3S) -N1- [2- [5-chloro-1- (p-tolylsul). Ponyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] cyclohexane-1,3-diamine (20c) (0.25 g, 0.43 mmol, 81% ) Provides a free base.

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Formation of amino] cyclohexyl] acetamide (547)

(1R, 3S) -N1- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4 -Yl] cyclohexane-1,3-diamine (20c) (0.050 g, 0.097 mmol) was dissolved in THF (1.0 mL), triethylamine (0.041 mL, 0.290 mmol) and acetyl chloride (0.013 mL, 0.190 mmol) ). After stirring overnight, the solvent was evaporated and the residue was taken up in THF (1.0 mL) and treated with 1M LiOH (1.0 mL, 1.0 mmol). The reaction mixture was heated to 130 ° C. for 10 minutes in microwave. The solvent was evaporated under reduced pressure and the residue was purified by HPLC using 5% -70% H ₂ O / acetonitrile + 0.1% TFA. The purified fractions were concentrated to dryness to provide the TFA salt of the product, which was dissolved in MeOH and passed through a polymer bound carbonate cartridge to provide the free base of the product 547.

The following compounds can be prepared by methods analogous to those described in Scheme 19 and Scheme 20:

(1R, 3S) -N1- [2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] cyclohexane-1 , 3-diamine (542)

LCMS RT = 1.4 (M + 1) 361.4.

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] acetamide (576)

LCMS RT = 1.8 (M + 1) 403 (M-1) 401.4.

Methyl N-[(1S, 3R) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] Amino] cyclohexyl] carbamate (548)

LCMS RT = 2.8 (M + 1) 419.5.

3-[(1S, 3R) -3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -1,1-dimethyl-urea (549)

LCMS RT = 2.6 (M + 1) 432.5.

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -2-methoxy-acetamide (591)

2-methoxyethyl N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidine -4-yl] amino] cyclohexyl] carbamate (592)

Scheme 21:

(a) tetrahydrofuran-2-carboxylic acid, EDC, HOBt, DIPEA, CH ₂ Cl ₂ , rt (b) LiOH, 130 ° C., microwave

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Formation of amino] cyclohexyl] tetrahydrofuran-2-carboxamide hydrochloride (638)

(1S, 3R) -N1- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl]-in CH ₂ Cl ₂ (3 mL)- In a solution of 5-fluoro-pyrimidin-4-yl] cyclohexane-1,3-diamine (20c) (60 mg, 0.12 mmol), tetrahydrofuran-2-carboxylic acid (20.3 mg, 0.17 mmol), EDC ( 26.8 mg, 0.14 mmol), HOBt (17.8 mg, 0.12 mmol) and DIPEA (60.2 mg, 0.47 mmol) were added and the reaction mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in THF (4 mL) and treated with 1M aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated to 130 ° C. for 20 minutes in microwave. The solvent was evaporated under reduced pressure and the residue was purified over 15 minutes by HPLC using 5-70% MeOH // H ₂ O + 6 mM HCl. The purified fractions were concentrated to N-[(1R, 3S) -3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyri A hydrochloride of midin-4-yl] amino] cyclohexyl] tetrahydrofuran-2-carboxamide 638 was provided.

The following compounds can be prepared by methods analogous to those described in Scheme 19, Scheme 20 and Scheme 21:

(1R, 3S) -N1- [2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] cyclohexane-1 , 3-diamine (542)

LCMS RT = 1.4 (M + 1) 361.4.

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] acetamide (576)

Methyl N-[(1S, 3R) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] Amino] cyclohexyl] carbamate (548)

LCMS RT = 2.8 (M + 1) 419.5.

3-[(1S, 3R) -3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -1,1-dimethyl-urea (549)

LCMS RT = 2.6 (M + 1) 432.5.

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -2-methoxy-acetamide (591)

2-methoxyethyl N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidine -4-yl] amino] cyclohexyl] carbamate (592)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -3-hydroxy-2,2-dimethyl-propanamide hydrochloride (650)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] tetrahydropyran-3-carboxamide hydrochloride (633)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -3-hydroxy-propanamide hydrochloride (634)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -3-methyl-oxetane-3-carboxamide hydrochloride (635)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] tetrahydropyran-4-carboxamide hydrochloride (636)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -3-hydroxy-butanamide hydrochloride (640)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] -2-hydroxy-propanamide hydrochloride (642)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] tetrahydropyran-2-carboxamide hydrochloride (651)

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] tetrahydrofuran-3-carboxamide hydrochloride (652)

(S) -tetrahydrofuran-3-yl (1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyripy Midin-4-ylamino) cyclohexylcarbamate (649)

LCMS RT = 3.3 (M + 1) 475.37, (M-1) 473.35.

N-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclo Hexyl) -3-methoxypropanamide (611)

LCMS RT = 2.0 (M + 1) 447.4, (M-1) 445.4.

N- [2- (5-chloro-lH-pyrrolo [5,4-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] cyclohexane-cis-1,3-diamine (540)

LCMS RT = 1.4 (M + 1) 361.5.

N- [cis-3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl] amino] cyclohexyl] Acetamide (452)

(Prepared from cis / trans 1,3diamino cyclohexane; separated by HPLC from trans diastereomers)

LCMS RT = 1.3 (M + 1) 403.1 (M-1) 401.1.

N- [trans-3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl Acetamide Acetamide (457)

(Separated by HPLC from cis diastereomers)

LCMS RT = 1.6 (M + 1) 403.2 (M-1) 401.1.

1- [cis-3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -3-methyl-urea (455)

(Prepared from cis / trans 1,3diamino cyclohexane; separated by HPLC from trans diastereomers)

LCMS RT = 1.7 (M + 1) 416.2.

1- [trans-3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -3-methyl-urea (458)

(Prepared from cis / trans 1,3-diamino cyclohexane; separated by HPLC from cis diastereomer)

LCMS RT = 0.8 (M + 1) 418.2 (M-1) 416.1.

3- [cis-3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -1,1-dimethyl-urea (456)

(Prepared from cis / trans 1,3diamino cyclohexane; separated by HPLC from trans diastereomers)

LCMS RT = 1.5 (M + 1) 432.2 (M-1) 430.2.

3- [trans-3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl ] -1,1-dimethyl-urea (459)

(Prepared from cis / trans 1,3diamino cyclohexane; separated by HPLC from cis diastereomer)

LCMS RT = 1.5 (M + 1) 432.2 (M-1) 430.2.

Methyl-cis-3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexylcarba Mate 514-(racemic cis mixture-made from cis-1,3-diaminocyclohexane)

LCMS RT = 1.3 (M + 1) 418.8.

N-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclo Hexyl) morpholine-4-carboxamide (647)

LCMS RT = 3.6 (M + 1) 474.4 (M-1) 472.5.

N- [3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl] methane Sulfonamide (454)

LCMS RT = 1.6 (M + 1) 439.1 (M-1) 437.1.

(Tetrahydrofuran-3-yl) methyl (1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine 4-ylamino) cyclohexylcarbamate (648)

LCMS RT = 3.7 (M + l) 489.38, (M-1) 487.49.

Scheme 22:

(a) 4-tert-butoxycarbonylmorpholine-2-carboxylic acid, EDC, HOBt, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ , rt (b) CH ₂ Cl ₂ , TFA (c) LiOH, 130 ° C. , Microwave

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Formation of amino] cyclohexyl] morpholine-2-carboxamide bishydrochloride (637)

(1S, 3R) -N1- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl]-in CH ₂ Cl ₂ (3 mL)- 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17) in a solution of 5-fluoro-pyrimidin-4-yl] cyclohexane-1,3-diamine (0.06 g, 0.12 mmol) mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and ⁱ Pr ₂ NEt (0.06 g, 0.47 mmol) were added and the reaction mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ (2 mL) and TFA (2 mL) and stirred at rt for 2 h. The resulting solution was concentrated in vacuo, dissolved in THF (4 mL) and treated with 1N aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated to 130 ° C. for 20 minutes in microwave. The solvent was evaporated under reduced pressure and the residue was purified over 15 minutes by HPLC using 5-70% MeOH / H ₂ O + 6 mM HCl. The purified fractions were concentrated to N-[(1R, 3S) -3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyri Bis-hydrochloride of midin-4-yl] amino] cyclohexyl] morpholine-2-carboxamide was provided.

Other homologues that may be prepared in the same manner as compound 637:

N-[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] Amino] cyclohexyl] piperidine-4-carboxamide bishydrochloride (639)

Scheme 23

(a) (1S, 2S) -cyclohexane-1,2-diamine, THF, 120 ° C. microwave (b) methyl-chloroformate, ⁱ Pr ₂ NEt, CH ₂ Cl ₂ (c) LiAlH ₄ , THF.

(1S, 2S) -N1- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclo Formation of Hexane-1,2-diamine (23b)

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] in THF (4 mL) A solution of pyridine (23a) (0.50 g, 1.08 mmol) was diluted with (1S, 2S) -cyclohexane-1,2-diamine (0.27 g, 2.37 mmol) and ⁱ Pr ₂ NEt (2.15 mmol) at 120 ° C. for 10 minutes. Treated. The mixture was concentrated in vacuo. The residue obtained was purified by silica gel chromatography (0-20% MeOH-CH ₂ Cl ₂ ) to afford the desired intermediate as a white solid (410 mg).

LCMS RT = 2.2 (M + 1) 515.5.

Methyl (1S, 2S) -2- (2- (5-Chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl Formation of amino) cyclohexylcarbamate (23c)

(1S, 2S) -N1- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in dichloromethane (4 mL) at room temperature To a mixture of ropyrimidin-4-yl) cyclohexane-1,2-diamine (23b) (0.18 g, 0.35 mmol) ⁱ Pr ₂ NEt (0.12 mL, 0.70 mmol) was added, followed by methyl chloroformate ( 0.03 mL, 0.37 mmol) was added. After 35 minutes, the mixture is diluted with EtOAc, washed successively with saturated aqueous NH ₄ Cl and saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to be sufficiently pure for use in the subsequent reaction. The crude product was provided.

LCMS RT = 4.1 (M + 1) 573.4.

(1S, 2S) -N1- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N2-methylcyclo Formation of Hexane-1,2-diamine 522

Methyl (1S, 2S) -2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in THF (3 mL) at room temperature LiAlH ₄ (0.06 g, 1.66 mmol) was added to a stirred solution of tropyrimidin-4-ylamino) cyclohexylcarbamate (23c) (0.09 g, 0.16 mmol) and the mixture was stirred for an additional 2 hours at room temperature. I was. The reaction was quenched with 0.06 mL KOH (5% aqueous) followed by water (3 × 0.06 mL). Then additional Et ₂ O (6 mL) was added and stirring continued for 20 minutes. The milky suspension was filtered, washed with EtOAc and this cake washed with more EtOAc. The combined organic phases were concentrated in vacuo and purified by preparative HPLC, then preparative TLC to give the desired product as the free base, which was then converted to the HCl salt by treatment with HCl (4N in dioxane).

LCMS RT = 1.7 (M + 1) 375.5.

 Scheme 24

(a) NaCNBH ₃ , (CH ₂ O) _n , HOAc, CH ₃ CN

(1S, 2S) -N1- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N2, N2- Formation of Dimethylcyclohexane-1,2-diamine 523

(1S, 2S) -N1- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- in acetonitrile (1.6 mL) at room temperature To a mixture of 4-yl) cyclohexane-1,2-diamine (23b) (0.08 g, 0.22 mmol) was added formaldehyde (37% w / v 0.09 mL, 1.11 mmol), followed by NaCNBH ₃ (0.04 g, 0.56 mmol) was added. A jelly-like mixture formed and after 4 minutes the mixture became fluid again. After 4 hours, the reaction was quenched with 5 mL 2N NaOH and the mixture was stirred overnight. The mixture was diluted with EtOAc and stirred until all solids dissolved. The layers were extracted several times with EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Silica gel chromatography (0-15% MeOH-CH ₂ Cl ₂ ) followed by preparative HPLC provided the desired product which was converted to the corresponding HCl salt using HCl (4N in dioxane).

Scheme 25

(a) 2- (methoxymethyl) oxirane, methanol, 130 ° C., microwave (b) LiOH, 130 ° C., microwave

1-[[(1R, 3S) -3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] Amino] cyclohexyl] amino] -3-methoxy-propan-2-ol 610

(1S, 3R) -N1- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro in methanol (2 mL) To a solution of ro-pyrimidin-4-yl] cyclohexane-1,3-diamine (20c) (50 mg, 0.09 mmol) was added 2- (methoxymethyl) oxirane (9.4 mg, 0.11 mmol), The reaction mixture was heated to 140 ° C. for 10 minutes in microwave. 1M aqueous LiOH (1.0 mL, 1.0 mmol) was added and the reaction mixture was heated to 130 ° C. for 10 min in microwave. The solvent was evaporated under reduced pressure and the residue was purified over 15 minutes by HPLC using 5-70% CH ₃ CN // H ₂ O + 0.1% TFA. The purified fractions were concentrated, redissolved in MeOH and passed through a carbonate-PS column to give the desired product 1-[[(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2, 3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexyl] amino] -3-methoxy-propan-2-ol 610 was provided. .

Scheme 26

(a) 2-bromoacetamide, Na ₂ CO ₃ , DMF, rt (b) LiOH, 130 ° C., microwave.

2-[[1R, 3S) -3- [2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl] amino] Formation of Cyclohexylamino] -Acetamide (593)

(1S, 3R) -N1- [2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro in DMF (2 mL) 2-bromoacetamide (0.015 g, 0.100 mmol) and Na ₂ CO ₃ (0.021) in a solution of rho-pyrimidin-4-yl] cyclohexane-1,3-diamine (20c) (0.050 g, 0.100 mmol) g, 0.190 mmol) was added. The reaction mixture was stirred at rt overnight. 1 M aqueous lithium hydroxide (2.0 mL, 2.0 mmol) was added and the reaction mixture was heated to 130 ° C. for 10 min in microwave. The solvent was evaporated under reduced pressure and the residue was purified over 15 minutes by HPLC using 5-70% CH ₃ CN // H ₂ O + 0.1% TFA. The purified fractions were concentrated, redissolved in MeOH and passed through a carbonate-PS column to give the desired product 2-[[1R, 3S) -3- [2- (5-chloro-lH-pyrrolo [2,3- b] pyridin-3-yl) -5-fluoropyrimidin-4-yl] amino] cyclohexylamino] -acetamide (593) was provided.

Scheme 27

a) 3-aminocyclohexanol, ⁱ Pr ₂ NEt, THF, MW 130 ° C .; b) Ag ₂ O, CaSO ₄ , CH ₃ I, rt; c) sodium methoxide, THF.

(S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Formation of the ol 27a

5-chloro-3- (5-fluoro-4- (methylsulfonyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (1a) (1.09 in THF g, 2.34 mmol) and DIEA (0.60 g, 4.69 mmol) were added to a solution of 3-aminocyclohexanol (0.32 g, 2.82 mmol). The reaction mixture was heated to 130 ° C. for 10 minutes in microwave. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel chromatography to give 550 mg of the desired product (27a).

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S) -3-methoxycyclohexyl) pyrimidine Formation of 4-amine (27b)

Methyl iodide (0.20 g, 0.41 mmol) and 3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro To a suspension of -pyrimidin-4-yl] amino] -cyclohexanol (27a) (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol) and calcium sulfate (0.28 g, 2.04 (mmol)). The reaction mixture was stirred at rt for 18 h The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo The crude mixture obtained was purified by silica gel chromatography to give 120 mg of the desired product (27b). It was.

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S) -3-methoxycyclohexyl) pyrimidin-4-amine Formation of 552

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-N- (3-methoxycyclohexyl) pyridine in THF To the solution of midin-4-amine (27b) (0.08 g, 0.15 mmol) was added NaOMe drop. The reaction mixture was stirred for 20 minutes at room temperature. Ethyl acetate and brine were added to the reaction mixture. The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in CH ₃ CN / H ₂ O and the mixture was purified by preparative HPLC to give 23 mg of the desired product (552).

(3S) -3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol (524)

LCMS RT = 2.0 (M + 1) 362.48.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl ethylcarbamate (608)

LCMS RT = 2.9 (M + 1) 433.4.

Scheme 28

a) Dess-Martin periodinane, CH ₂ Cl ₂ ; b) CH ₃ MgBr, THF; c) sodium methoxide, THF.

3- (2- (5-chloro-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Formation of a warm 28a

3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine in 20 mL of CH ₂ Cl _2. To a solution of -4-yl] amino] cyclohexanol (27a) (0.54 g, 1.05 mmol) was added Dess-Martin periodinan (0.62 g, 1.47 mmol). This suspension was stirred for 6 hours at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel chromatography (45% ethyl acetate / hexane gradient) to give 430 mg of the desired product.

3- (2- (5-chloro-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1 Formation of Methylcyclohexanol (28b)

3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine- in THF (5 mL) To a cooled (0 ° C.) solution of 4-yl] amino] cyclohexanone (28a) (0.47 g, 0.92 mmol) was added methylmagnesium bromide (3.30 mL of 1.4 M solution, 4.58 mmol). The reaction mixture was stirred at 0 ° C for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous NH ₄ Cl solution. The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The product was purified by silica chromatography using DCM and methanol, and the two products eluted with 95% DCM and 5% methanol and did not separate. Two diastereomers were obtained as a mixture without further purification.

LCMS (10-90% 3/5 min (grad / run) w / FA) showed two peaks for the desired product. Peak 1: retention time = 4.04 min (M + 1: 530.42); Peak 2: Retention time = 4.18 min (M + 1: 530.45).

(3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexane Formation of all 571 and 572

3- (2- (5-chloro-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) in THF) To a solution of -1-methylcyclohexanol (28b) was added 25% sodium methoxide drop at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with ethyl acetate and brine. The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The product was purified by preparative HPLC to give two diastereomers.

Diastereomers 1-571:

Diastereomers 2-572:

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethynylcyclohexanol (617 And 618)

Diastereomers 1-617: LCMS RT = 3.6 (M + 1) 386.4.

Diastereomers 2-618: LCMS RT = 3.2 (M + 1) 386.3.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-vinylcyclohexanol (627 and 628)

Diastereomers 1-627: LCMS RT = 4.0 (M + 1) 388.4.

Diastereomers 2-628: LCMS RT = 3.7 (M + 1) 388.4.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (hydroxymethyl) cyclohexane All (646)

LCMS RT = 3.4 (M + 1) 392.4.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcyclohexanol 626

LCMS RT = 4.1 (M + 1) 390.4.

Scheme 29

Formation of (3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (29a)

(3S) -3-aminocyclohexanol, the starting racemic alcohol, is described by Bernardelli, P., Bladon, M., Lorthiois, E., Manage, A., Vergne, F. and Wrigglesworth, R., Tetrahedron Asymmetry 2004, 15, 1451-1455.

(3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol was prepared using (3S) -3-aminocyclohexanol according to the method for compound (16a). Prepared by obtaining the product 29a as a solid.

Formation of (S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone (29b)

700 of (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanol (29a) (7.90 g, 32.16 mmol) in CH ₂ Cl ₂ (700 mL) Des-Martin reagent (17.73 g, 41.81 mmol) was added to the ml DCM solution. The reaction mixture was stirred at rt for 20 h until TLC chromatography indicated the reaction was complete. The reaction mixture was filtered through a pad of celite and the filtrate obtained was washed with 200 ml of saturated aqueous NaHCO ₃ and 200 ml of brine. The organic phase was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. The product was purified by silica gel chromatography (50% EtOAc / hexanes) to give 7.3 g (93% yield) of the desired product (29b).

Formation of (3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (29c, 29d)

Magnesium bromide at room temperature in a solution of (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanone (1.83 g, 7.49 mmol) in THF (100 mL) (21.4 mL 1.4M solution, 29.96 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added saturated aqueous NH ₄ Cl solution and EtOAc. The organic phase was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Two spots were separated by silica gel chromatography (120 g silica gel column).

Fraction-1 (29c):

Fraction-2 (29d):

(3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1 Formation of methylcyclohexanol (29e, 29f)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in dimethoxyethane (15 mL) ) Pyrrolo [2,3-b] pyridine (1.46 g, 3.37 mmol), (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] -1-methyl- A solution of cyclohexanol (29c) (0.72 g, 2.81 mmol) and Na ₂ CO ₃ (4.21 mL of 2M solution, 8.433 mmol) was degassed with nitrogen for 30 minutes. Palladium tetrakis-triphenylphosphane (0.16 g, 0.14 mmol) was added to this reaction mixture. The reaction mixture was heated to 130 ° C. for 45 minutes in a Q-tube apparatus. The reaction mixture was filtered through a pad of 1 cm silica gel and 2 cm celite. The product was purified by silica gel chromatography (hexane / EtOAc) to give the desired product (29e) (yield 63%).

Diastereomers 29f were prepared according to the same method as compound 29e, using compound 29d as the starting material for the Suzuki coupling process.

(3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1 Formation of Methylcyclohexanol (655, 656)

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro in THF (200 mL) To a solution of -pyrimidin-4-yl] amino] -1-methyl-cyclohexanol (29f) (2.85 g, 5.38 mmol) was added 1.5 ml of a 25% w / w sodium methoxide solution at room temperature. The reaction mixture was immediately injected into LC / MS. LC / MS showed the reaction was complete. The reaction mixture was diluted with 200 mL EtOAc and the organic phase was washed twice with saturated aqueous NaHCO ₃ solution and then twice with brine. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by silica gel chromatography (80 g silica, 5% MeOH / CH ₂ Cl ₂ ) to give 1.7 g of the desired product. The obtained product was dissolved in 70 mL of THF, and 1.8 mL of 5M HCl / IPA was added thereto. The resulting suspension was stirred at rt for 1 h. The solvent was removed under reduced pressure to afford 1.7 g of the desired product (655) as an HCl salt.

Corresponding diastereomers 656 may be prepared in the same manner.

Scheme 30

(a) mCPBA, CH ₂ Cl ₂ (b) NH 4 OH, water, 50 ° C., 72 hours (c) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, ⁱ Pr ₂ NEt, DMF, 90 ° C., 17 h (d) 1N LiOH, THF, microwave, 120 ° C., 10 min.

Formation of 1-methyl-7-oxabicyclo [4.1.0] heptane (30a)

To a cooled (0 ° C.) solution of 1-methylcyclohexene (3.0 g, 31.2 mmol) in CH ₂ Cl ₂ (150 mL) was added mCPBA (8.4 g, 48.7 mmol). The reaction mixture was stirred at 0 ° C for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted with ether. The organic phase was washed again with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the desired product as an oil used without further purification.

Formation of 2-amino-1-methylcyclohexanol (30b)

Ammonium hydroxide (6.0 mL, 154.1 mmol) was added to a solution of 1-methyl-7-oxabicyclo [4.1.0] heptane (30a) (1.0 g, 7.1 mmol) in water. The mixture was heated to 50 ° C. for 48 hours. The mixture was diluted with water, extracted with EtOAc and then extracted twice with 20% MeOH / CHCl ₃ . The organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the desired product 30b as an amorphous white solid.

2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexane Formation of the ol 30c

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] in DMF (10 mL) ^I Pr ₂ NEt (0.73 mL, 4.17 mmol) was added to a solution of pyridine (1a) (0.97 g, 2.09 mmol) and 2-amino-1-methylcyclohexanol (30b) (0.40 g, 3.13 mmol). The reaction mixture was heated to 90 ° C. for 17 hours. The reaction mixture was cooled to room temperature and diluted in saturated aqueous NaCl solution. The aqueous phase was extracted twice with EtOAc. The organic phases were washed twice with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (loaded with 0-50% EtOAc / hexanes —CH ₂ Cl ₂ ) to afford the desired product (30c) as a white solid.

LCMS RT = 4.1 (M + 1) 530.6.

2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (562 and 563) Formation

2-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] in THF To a solution of amino] -1-methyl-cyclohexanol (30c) (0.41 g, 0.77 mmol) was added 1 M LiOH solution. The reaction mixture was heated to 120 ° C. for 5 minutes in microwave. The reaction mixture was diluted with water and extracted twice with EtOAc, then twice with 10% MeOH / CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (5-20% MeOH: CH ₂ Cl ₂ ) to give a white solid as a mixture of trans-enantiomers. Two trans-enantiomers were separated by chiral preparative HPLC to yield compound (562) and compound (563).

Enantiomers 1-563:

Scheme 31

(a) 2,4-dichloro-5-fluoropyrimidine, acetonitrile / isopropanol, reflux 1.5 hours (b) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, Pd (PPh ₃ ) ₄ , 2M Na ₂ CO ₃ , acetonitrile, 120 ° C. microwave 15 minutes , (c) TBAF, THF.

Formation of (1R, 2S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1,2-diol (31b)

(1R, 2S, 3S) -3-aminocyclohexane-1,2-diol as starting racemic diol (31a) is described in Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al.]. To a solution of racemic diol (31a) (0.66 g, 5.00 mmol) in acetonitrile (5 mL) and isopropanol (5 mL), 2,4-dichloro-5-fluoro-pyrimidine (0.84 g, 5.03 mmol) and ⁱ Pr ₂ NEt (3.25 g, 4.38 mL, 25.20 mmol) was added. The reaction mixture was sealed and heated to 100 ° C. for 90 minutes and then concentrated to dryness. The crude material was purified via silica gel chromatography (40% -100% EtOAc / Hex) to give a racemate which was further purified via chiral HPLC separation to give compound 31b (0.26 g) as a white solid. Obtained.

LCMS RT = 2.8 (M + 1) 262.0, (M-1) 260.1.

(1R, 2S, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) cyclohexane-1,2-diol (31c)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in acetonitrile (6 mL) Pyrrolo [2,3-b] pyridine (0.22 g, 0.51 mmol) and (1R, 2S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1, To a deoxygenated solution of 2-diol (31b) (0.08 g, 0.24 mmol) 2M sodium carbonate (0.45 mL, 0.894 mmol) and Pd (PPh ₃ ) ₄ (34.5 mg, 0.030 mmol) were added. The reaction was sealed and heated to 120 ° C. for 15 minutes in microwave. The reaction was diluted with EtOAc and filtered through Florisil. The solution was concentrated to give crude material, which was purified by silica gel chromatography (DCM → 20% MeOH / DCM) to give compound 31c (0.11 g) as a pink solid.

LCMS RT = 3.8 (M + 1) 532.2, (M-1) 530.2.

(1R, 2S, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Formation of -1,2-diol 632

(1R, 2S, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 in THF To a solution of -ylamino) cyclohexane-1,2-diol (31c) (0.11 g, 0.21 mmol) TBAF (0.23 g, 0.84 mmol) was added. The reaction was aged at rt for 1 h, quenched with 1N HCl (1 mL) and purified via reverse phase chromatography (5-70% MeCN / H ₂ 0 + 0.1% TFA). The product was desalted on an SPE bicarbonate cartridge, concentrated to dryness and triturated with MeOH to give 18 mg of compound 632.

LCMS RT = 3.0 (M + 1) 378.2, (M-1) 376.0.

Scheme 32

(a) 2,4-dichloro-5-fluoropyrimidine, acetonitrile, isopropanol, reflux 1.5 hours (b) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, Pd (PPh ₃ ) ₄ , 2M Na ₂ CO ₃ , acetonitrile, 120 ° C. microwave, 15 Min, (c) TBAF, THF

Formation of (1S, 2S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1,2-diol (32b)

(1S, 2S, 3S) -3-aminocyclohexane-1,2-diol as starting racemic diol (32a) is described in Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al.]. Compound 32b (0.03 g, 0.11 mmol) was obtained as a white solid, according to the method for compound 632, except that a racemate of diol 32a (0.07 g, 0.53 mmol) was used.

LCMS RT = 2.7 (M + 1) 262.0.

(1S, 2S, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) cyclohexane-1,2-diol (32c)

Except for using Compound 32b (0.03 g, 0.11 mmol), according to the method for Compound 31c, Compound 32c (0.06 g, 0.11 mmol) was obtained.

LCMS RT = 3.9 (M + 1) 532.2, (M-1) 530.3.

(1S, 2S, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Formation of -1,2-diol 615

Except for using Compound 32c (0.06 g, 0.11 mmol), according to the method for Compound 624, Compound 615 (0.015 g, 0.035 mmol) was obtained as a white solid.

LCMS RT = 3.7 (M + 1) 378.3, (M-1) 376.3.

Scheme 33

(a) 2,4-dichloro-5-fluoropyrimidine, acetonitrile, isopropanol, reflux 1.5 hours (b) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, Pd (PPh ₃ ) ₄ , 2M Na ₂ CO ₃ , acetonitrile, 120 ° C. microwave, 15 Min, (c) TBAF, THF.

Formation of (1R, 2R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1,2-diol (33b)

(1R, 2R, 3S) -3-aminocyclohexane-1,2-diol as starting racemic diol (33a) is described in Org. Lett. (2009) 6, 1333, Davies, et. al.]. Compound 33b (0.14 g, 0.53 mmol) was obtained as a white solid, according to the method for compound 632, except that a racemate of diol 33a (0.13 g, 1.01 mmol) was used.

LCMS RT = 2.4 (M + 1) 262.0, (M-1) 260.1.

(1R, 2R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) cyclohexane-1,2-diol (33c)

Except for using Compound 33b (0.07 g, 0.26 mmol), according to the method for Compound 31c, Compound 33c (0.008 g, 0.015 mmol) was obtained. DME was used instead of acetonitrile as the solvent.

LCMS RT = 4.2 (M + 1) 532.3, (M-1) 530.3.

(1R, 2R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Formation of -1,2-diol 625

Compound 625 (0.005 g, 0.012 mmol) was obtained according to the method for compound 624, except that compound 33c (0.008 g, 0.015 mmol) was used.

LCMS RT = 2.4 (M + 1) 378.2, (M-1) 376.2.

The following compounds 631, 616 and 624 are enantiomers of compounds 632, 615 and 625, which can be prepared by isolating by chiral preparative HPLC chromatography from their respective enantiomeric mixtures.

Scheme 35

(a) (1S, 2S) -2-aminocyclohexanecarboxylic acid, ⁱ Pr ₂ NEt, Na ₂ CO ₃ , THF-CH ₃ CN (3: 1), 135 ° C. microwave; (b) 1N LiOH, THF, microwave, 120 ° C. (c) 4N HCl-dioxane, EtOH, 70 ° C.

(1S, 2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ( 553) Formation

5-chloro-3- (5-fluoro-4-methylsulfonyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pi in THF (10 mL) and CH ₃ CN (2 mL) Rolo [2,3-b] pyridine (1a) (0.49 g, 1.05 mmol), (1S, 2S) -2-amino-cyclohexanecarboxylic acid (0.30 g, 2.10 mmol), freshly ground Na ₂ CO ₃ (0.22 g, 2.10 mmol) and ⁱ Pr ₂ NEt (0.37 mL, 2.10 mmol) were heated to 130 ° C. for 30 minutes under microwave irradiation in a closed vessel. The mixture was cooled to room temperature. 1N LiOH solution (3.1 mL, 3.1 mmol) was added and the mixture was stirred for 10 min at 120 ° C. under microwave irradiation. The mixture was acidified to pH 2 with 1N HCl under vigorous stirring. The newly formed solid was recovered by vacuum filtration. The solid was washed with a little water and EtOAc. The solid was dried in vacuo to give the desired product.

Other homologues which may be prepared in the same manner as compound 553 are described below:

Trans-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (541)

LCMS RT = 2.4 min, (M + H) 390.5.

(1R, 2R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ( 554)

LCMS RT = 2.3 min, (M + H) 390.4.

Cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (559)

LCMS RT = 2.3 min, (M + H) 389.8.

(1S, 2R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ( 579)

LCMS RT = 2.9 min, (M + H) 390.4.

(1R, 2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ( 578)

LCMS RT = 2.8 min, (M + H) 390.4.

Cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanecarboxylic acid (558)

LCMS RT = 2.5 min, (M + H) 376.2.

(1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanecarboxylic acid ( 566)

LCMS RT = 2.3 min, (M + H) 376.4.

(1S, 3R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanecarboxylic acid ( 565)

LCMS RT = 2.4 min, (M + H) 376.4.

(1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ( 630)

Compound 630 was prepared in the same manner from intermediate 18c by removing the Cbz-protecting group, reacting with intermediate 1a, and then removing the tosyl protecting group.

LCMS RT = 3.2 min, (M + H) 390.4, (M-H) 388.1.

Trans-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylic acid ( 582)

LCMS RT = 3.2 min, (M + H) 404.4.

Racemic trans-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcyclohexane Carboxylic acid (586)

LCMS RT = 2.9 min, (M + H) 418.4.

Racemic cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcyclohexane Carboxylic Acid (585)

LCMS RT = 3.2 min, (M + H) 418.4.

(3S, 4R, 5R) -Ethyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino)- 4-ethaneamido-5- (pentan-3-yloxy) cyclohex-1-enecarboxylate (670)

LCMS RT = 3.6 (M + 1) 559.4.

(3S, 4R, 5R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -4 Ethaneamido-5- (pentan-3-yloxy) cyclohex-1-enecarboxylic acid (671)

LCMS RT = 3.1 (M + 1) 531.4.

Scheme 36

(1S, 2S) -ethyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxyl Rate (561)

(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [5,4-b] pyridin-3-yl) -5-fluoro-pyrimidine in ethanol (1.5 mL) at room temperature To a mixed slurry of -4-yl] amino] cyclohexane-1-carboxylic acid (553) (0.090 g, 0.231 mmol) was added HCl (0.577 mL of 4M solution, 2.309 mmol). The solution was raised to 50 ° C. After 6 h the mixture was basified with 1N NaOH, brine was added and the aqueous layer was extracted repeatedly with EtOAc. The organic layer was dried over MgSO ₄ , filtered through a short plug of silica gel and concentrated in vacuo to give the desired product.

LCMS RT = 2.7 min, (M + H) 418.4.

The following compounds can also be prepared in a similar manner as described in Scheme 36.

(1R, 2R) -ethyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxyl Rate (560)

LCMS RT = 3.2 min, (M + H) 418.5.

(1S, 2S) -Methyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxyl Rate (575)

LCMS RT = 3.1 min, (M + H) 404.4.

(1S, 2S) -2-methoxyethyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino Cyclohexanecarboxylate (574)

LCMS RT = 3.0 min, (M + H) 448.4.

(1R, 2R) -Isopropyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Carboxylate (568)

LCMS RT = 3.08 min, (M + H) 432.46.

(1S, 2S) -isopropyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane Carboxylate (569)

LCMS RT = 2.7 min, (M + H) 432.5.

Scheme 37

Preparation of cis-2-amino-1-methylcyclohexanecarboxylic acid (37c)

(a) NaH, iodomethane DMF (b) NH ₂ OH-HCl, pyridine, EtOH (c) Al (Hg), THF-H ₂ O (4: 1).

Formation of ethyl 1-methyl-2-oxocyclohexanecarboxylate (37a)

The title compound was prepared according to the method described in Tetrahedron Letters (2005) 46, 681-685 and JCS, Perkin Trans 1 (2000) 3277-3289.

Sodium hydride (1.48 g, 37.14 mmol, 60% in oil) was washed twice with hexane to remove the oil and suspended in DMF (57 mL) at 0 ° C. Then ethyl 2-oxocyclohexanecarboxylate (5.40 mL, 33.76 mmol) was added over 5 minutes. The mixture was stirred for 20 minutes and MeI (2.21 mL, 35.45 mmol) was added over 10 minutes. The mixture was warmed to rt and after 30 min diluted with EtOAc (150 mL) and quenched with saturated NH ₄ Cl. The layers were separated and the aqueous layer was extracted twice more with EtOAc (2 × 100 mL). The organic layer was washed with brine (twice), dried over MgSO ₄ , filtered through silica gel and concentrated to give the desired product 37a.

Formation of 3a-methyl-4,5,6,7-tetrahydrobenzo [c] isoxazol-3 (3aH) -one (37b)

To a mixture of ethyl 1-methyl-2-oxo-cyclohexanecarboxylate (37a) (2.05 g, 11.10 mmol) in EtOH (20 mL), hydroxylamine hydrochloride (0.97 g, 13.96 mmol) and pyridine (0.99 mL, 12.20 mmol) was added. The mixture was heated to 65 ° C. overnight. The solution was concentrated in vacuo and the crude material partitioned between water and EtOAc. The aqueous layer was extracted twice more with EtOAc. The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (0-35% EtOAc / hexanes) to afford the desired product (37b).

Formation of trans-2-amino-1-methylcyclohexanecarboxylic acid (37c)

3a-methyl-4,5,6,7-tetrahydro-2,1-benzoxazol-3-one (37b) (0.075 g, 0.490 mmol) in THF-H ₂ O (2.5 mL of 4: 1 mixture) at room temperature Fresh Al (Hg) amalgam was added to the solution. Aluminum was amalgamated by immersing a small strip of aluminum foil in a 2% HgCl ₂ solution and washing with water and EtOH. After 1 hour, 65 mg of Al (Hg) was further added and the mixture was stirred overnight. The thick gray emulsion formed was filtered through celite and washed with water and THF. The clear solution is concentrated in vacuo, stripped with methanol and THF to remove residual water, and concentrated in vacuo to give the desired product as a mixture of trans isomers and cis isomers (~ 9: 1) (trans isomer predominant isomers). Served as. The product was pure enough for use in subsequent reactions.

FIA (M + H) 158.1, (M-H) 156.2.

Formation of 2-amino-1-ethylcyclohexanecarboxylic acid

The compound was prepared as an inseparable mixture (70:30) of cis and trans isomers by the method described above and used without further purification.

Scheme 38

Preparation of cis-2-amino-1-alkyl-cyclohexanecarboxylic acid

(a) LDA, iodoethane, THF (b) H ₂ , Pd-C, MeOH

Alternative schemes for the preparation of cis-2-amino-1-alkyl-cyclohexanecarboxylic acids are illustrated above. The method is described in (a) Nemoto, T .; Fukuyama, T .; Yamamoto, E .; Tamura, S .; Fukuda, T .; Matsumoto, T .; Akimoto, Y .; Hamada, Y. Org. Lett. 2007, 9 (5), 927-930. (b) Seebach, D ,; Estermann, H. Tetrahedron Lett. 1987, 28 (27), 3103-3106.

(1R, 2S) -Methyl 2- (benzyloxycarbonylamino) -1-ethylcyclohexanecarboxylate (38b)

N-butyllithium (3.43 mL, 5.49 mmol) was added dropwise to a cooled (−78 ° C.) solution of N-isopropylpropan-2-amine (0.77 mL, 5.49 mmol) in THF (7 mL). The mixture was stirred at -78 ° C for 10 minutes. Then a solution of methyl (1S, 2S) -2-benzyloxycarbonylaminocyclohexanecarboxylate (38a) (0.40 g, 1.37 mmol) in THF (2.5 mL) was added over a period of 3 minutes. After 15 minutes, the mixture was allowed to warm slightly for 15 minutes (-40 ° C.) and again cooled to −78 ° C. for 10 minutes. Iodoethane (0.86 g, 0.44 mL, 5.49 mmol) was then added dropwise over 3 to 5 minutes. The reaction mixture was kept at −78 ° C. for 2 hours and warmed to room temperature overnight. The reaction was quenched with 5 mL saturated aqueous NH ₄ Cl aqueous solution, extracted with EtOAc (3 times) and washed successively with 1N HCl and brine. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Flash chromatography (SiO ₂ , 0-20% EA / Hex slow gradient elution) gave 275 mg (63% yield) of the desired product (38b). NMR showed a diastereomeric ratio above 10 to 1 (cis to trans).

(1R, 2S) -Methyl 2-amino-1-ethylcyclohexanecarboxylate (38c)

A solution of methyl (1R, 2S) -2-benzyloxycarbonylamino-1-ethyl-cyclohexanecarboxylate (38b) (0.27 g, 0.85 mmol) in MeOH (7.5 mL) was purged with nitrogen and a catalytic amount of Pd (5% carbon supported Pd) was added. The solution was placed under H ₂ atmosphere and stirred at room temperature. After 1 h, the MeOH solution suspension was filtered through celite and concentrated in vacuo to give the desired product (138 mg, yield 88%). The material was diluted with acetonitrile and concentrated to remove residual methanol.

Scheme 39

Preparation of trans-2-amino-1-alkyl-cyclohexanecarboxylic acid

(a) benzyl alcohol, toluene, 4 'sieve, reflux (b) NaH, MeI, DMF (c) benzylamine, TiCl ₄ , CH ₂ Cl ₂ , then NaCNBH ₃ , MeOH, 0 ° C. (d) H ₂ , Pd- C, MeOH (e) 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] Pyridine, Na ₂ CO ₃ , THF / CH ₃ CN, microwave irradiation 135 ° C. (f) HCl, CH ₃ CN, dioxane, 80 ° C.

The general method for the synthesis of trans-2-amino-1-alkyl-cyclohexanecarboxylic acid is shown in the above scheme.

Benzyl 2-oxocyclohexanecarboxylate (39b)

The compound is described in Matsuo, J. et al. Tetrahedon: Asymmetry 2007, 18, 1906-1910].

Benzyl 1-methyl-2-oxocyclohexanecarboxylate (39c)

The compound is described in (a) Hayashi, Y .; Shoji, M .; Kishida, S. Tetrahedron Lett. 2005, 46, 681-685. Winfield, C. J .; Al-Mahrizy, Z .; Gravestock, M .; Bugg, T. D. H. J. Chem. Soc., Perkin Trans. 1, 2000, 3277.

Trans-benzyl 2- (benzylamino) -1-methylcyclohexanecarboxylate (39d) (racemic trans)

Dichloromethane (10.0㎖) of 1-benzyl-2-oxo-cyclohexane carboxylate (39c) (0.50g, 2.03mmol) and benzylamine TiCl ₄ at room temperature to a solution of (0.61g, 0.63㎖, 5.75mmol) (1.93 mL of 1.M solution, 1.93 mmol) was added dropwise. The mixture was stirred for 2 hours. The mixture was cooled to 0 ° C. and a solution of NaBH ₃ CN (0.21 g, 3.34 mmol) in MeOH was added dropwise over a period of 3 minutes. After 15 minutes, the solution was warmed to room temperature and stirred for 45 minutes further. The mixture was then diluted with EtOAc and quenched with 10 mL 1M NaOH. The mixture was partitioned with Et ₂ O and the aqueous layer was extracted several times with Et ₂ O (twice) and EtOAc (once). The combined organic phases were dried over MgSO ₄ , filtered and concentrated in vacuo. Flash chromatography (SiO ₂ , 0-50% EtOAc-hexane gradient elution) and isolation of the main components provided the desired product (320 mg) as a single racemic trans isomer.

Trans-2-amino-1-methylcyclohexanecarboxylic acid (39e)

Pd (5% carbon) in a solution of racemic trans-benzyl (1S, 2S) -2- (benzylamino) -1-ethyl-cyclohexanecarboxylate (39d) (0.32 g, 0.91 mmol) in MeOH (12.8 mL) Supported Pd, 0.07 g) was added. The solution was degassed and left overnight under 50 PSI H ₂ (Far Shaker). The mixture was filtered through celite and the filtrate was washed with MeOH. After the mother liquor was concentrated, the remaining MeOH was removed by acetonitrile azeotrope (twice) to give the desired product (162 mg).

Trans-2-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] Amino] -1-methyl-cyclohexanecarboxylic acid (39f)

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (15a) (0.27 g, 0.58 mmol), anhydrous in a container filled with trans-2-amino-1-methyl-cyclohexanecarboxylic acid (39e) (0.08 g, 0.47 mmol) and freshly ground Na ₂ CO ₃ (0.19 g, 1.75 mmol) THF (4.5 mL) and CH ₃ CN (0.9 mL) were added. The vessel was sealed and heated to 135 ° C. for 35 minutes (microwave irradiation). LC-MS showed complete consumption of starting material. Next, the reaction mixture was poured slowly into a vigorously stirred 1N HCl solution (13.5 mL). The pH of the final solution was 1-2. The mixture is extracted with EtOAc (3 times), dried over Na ₂ S0 ₄ , Filter through celite and concentrate in vacuo. Flash chromatography (SiO ₂ , 0-10% MeOH-dichloromethane, gradient elution) gave a viscous yellow foam which was suspended in acetonitrile. After sonication the solvent was evaporated to give a white amorphous solid (240 mg, yield 74%) as a racemic mixture of trans stereoisomers.

LCMS RT = 4.00 min, (M + H) 558.34.

Trans-2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] -1-methyl- Cyclohexanecarboxylic acid (643)

Racemic trans-2-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5- in CH ₃ CN (2.35 mL) To a slurry of fluoro-pyrimidin-4-yl] amino] -1-methyl-cyclohexanecarboxylic acid (39f) (0.047 g, 0.084 mmol) was added HCl in dioxane (1.26 mL of 4M solution, 5.05 mmol). The suspension became a clear solution. The vial was sealed and heated to 80 ° C. for 2 hours during which a thick slurry formed. The slurry was cooled to room temperature overnight. More CH ₃ CN was added and the mixture was centrifuged. The organic layer was discarded and the solid was triturated three more times with CH ₃ CN to give an amorphous white solid as a racemic mixture of trans stereoisomers.

LCMS RT = 3.30 min, (M + H) 404.36.

Scheme 40

a) tert-butylmagnesium chloride; I ₂ , Et ₃ N, THF, DME (b) 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxabo Rolan-2-yl) pyrrolo [2,3-b] pyridine, DME / H ₂ O, Na ₂ CO ₃ , tetrakis triphenylphosphinepalladium (0), 130 ° C., microwave (c) mCPBA, CH ₂ Cl ₂ (d) (1S, 2S) -2-aminocyclohexanecarboxylic acid, Na ₂ CO ₃ , THF-CH ₃ CN (3: 1), 150 ° C. microwave.

Formation of 4-tert-butyl-2-chloro-5-fluoro-6- (methylthio) pyrimidine (40a)

To a cooled (0 ° C.) solution of tert-butylmagnesium chloride (7.5 ml, 1M solution in THF, 7.5 mmol) in THF (15 ml) 2-chloro-5- in 1,2-dimethoxyethane (5 ml) A solution of fluoro-4- (methylthio) pyrimidine (0.9 g, 5.0 mmol) was added slowly. The reaction mixture was stirred at 15 ° C. for 1 hour, then cooled to 0 ° C., triethylamine (0.7 mL, 5.0 mmol) was added and then iodine (1.3 g, 5.0 mmol) in tetrahydrofuran (3 mL) Solution was added. Water (10 mL) was added to quench the reaction and the pH was adjusted to 1 with 6N hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (2x15 mL). The combined organic phases were washed with aqueous sodium thiosulfate and then brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give a brown solid which was used without further purification.

¹ H NMR (300.0 MHz, CDCl ₃ ) δ 2.52 (s, 3H), 1.30 (s, 9H) ppm.

LCMS (M + 1) 233.0.

Formation of 3- (tert-butyl-5-fluoro-6- (methylthio) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b] pyridine (40b)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5, in 1,2-dimethoxyethane (3 mL) and aqueous Na ₂ CO ₃ (0.75 mL of 2M solution, 1.5 mmol) 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (0.22 g, 0.50 mmol) and 4-tert-butyl-2-chloro-5 To a degassed solution of -fluoro-6-thiomethoxypyrimidine (40a) (0.12 g, 0.50 mmol) tetrakis (triphenylphosphine) palladium (0) (0.03 g, 0.03 mmol) was added. The reaction mixture was further degassed for 15 minutes. The mixture was heated to 150 ° C. for 20 minutes in a microwave. Ethyl acetate (15 mL) was added. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude residue obtained was purified by silica gel chromatography (0% -100% EtOAc / hexanes) to afford the desired product (40b) (47 mg).

LCMS (M + 1) 352.3.

Formation of 3- (tert-butyl-5-fluoro-6- (methylsulfinyl) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b] pyridine (40c)

3- (tert-butyl-5-fluoro-6- (methylthio) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b in CH ₂ Cl ₂ (3.4 mL) ] MCPBA (0.02 g, 0.11 mmol) was added to a solution of pyridine (40b) (0.05 g, 0.11 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and saturated NaHCO ₃ solution (5 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (10 mL). The combined organic phases were washed again with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the desired product which was used without further purification.

LCMS (M + 1) 368.3.

(1S, 2S) -2- (6-tert-butyl-2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4- Formation of monoamino) cyclohexanecarboxylic acid (629)

3- (tert-butyl-5-fluoro-6- (methylsulfinyl) pyrimidin-2-yl) -5-chloro-1H-pyrrolo in THF (1 mL) and CH ₃ CN (0.5 mL) [2,3-b] pyridine (40c) (0.05 g, 0.14 mmol), (1S, 2S) -2-amino-cyclohexanecarboxylic acid (0.04 g, 0.27 mmol), freshly ground Na ₂ CO ₃ (0.04 g , 0.41 mmol) and ⁱ Pr ₂ NEt (0.37 mL, 0.27 mmol) were heated to 140 ° C. for 30 minutes under microwave irradiation in a closed vessel. The mixture was cooled to room temperature. 1N HCl solution (0.5 mL, 0.5 mmol) was added and the mixture was concentrated to give a yellow solid, which was purified by reverse phase HPLC (0% -50% methanol / water) to yield the desired product (629) as an off-white solid. Obtained.

LCMS (M + 1) 446.23.

Scheme 41

(a) 3-amino-1-methylpyrrolidin-2-one, DMA, 140 ° C. microwave; (b) i: LiOH, THF, microwave, 120 ° C., or ii: NaOMe, MeOH.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylpyrrolidine-2- Formation of on 379

5-Chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] in DMA (0.5 mL) A solution of pyridine (15a) (0.060 g, 0.129 mmol) was treated with 3-amino-1-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reaction was heated to 140 ° C. for 20 minutes. The reaction mixture was cooled to room temperature, then treated with 0.5 mL of 25% NaOMe in MeOH and heated to 50 ° C. for 15 minutes. The mixture was then partitioned between saturated aqueous Na ₂ CO ₃ solution and EtOAc. The aqueous layer was extracted twice more with EtOAc and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product.

LCMS RT = 2.3 min, (M + H) 361.3.

The following compounds can also be prepared in a manner similar to that described in Scheme 41.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-2-one (380)

LCMS RT = 2.3 min, (M + H) 347.3.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylpiperi Din-2-one (397)

LCMS RT = 2.2 min, (M + H) 375.4.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-2- On (416)

LCMS RT = 1.6 min, (M + H) 361.3.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azepan-2-one (417)

LCMS RT = 1.7 min, (M + H) 375.4.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylpiperi Din-2-one (460)

LCMS RT = 2.0 min, (M + H) 389.1.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylazane 2-one (461)

LCMS RT = 2.0 min, (M + H) 389.1.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylazane 2-one (462)

LCMS RT = 3.3 min, (M + H) 403.4.

(R) -5-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) pyrrolidine 2-one (503)

LCMS RT = 2.2 min, (M + H) 361.2.

(S) -3- (5-fluoro-2- (5- (trifluoromethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) ase Pan-2-On (502)

LCMS RT = 2.3 min, (M + H) 409.

(S) -6- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -4- (4- Methoxybenzyl) -1,4-oxazepan-5-one (505)

LCMS RT = 3.1 min, (M + H) 497.7.

Starting amines for the compounds are described in Blizzard, Timothy A .; Chen, Helen Y .; Wu, Jane Yang; Kim, Seongkon; Ha, Sookhee; Mortko, Christopher J .; Variankaval, Narayan; Chiu, Anna. 7-Oxo-2,6-Diazabicyclo [3.2.0] heptane-6-sulfonic acid derivatives as b-lactamase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of bacterial infections. PCT Int. Appl. (2008), 101 pp. It was prepared according to established methods as described in WO2008039420.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) azepan-2-one (500)

LCMS RT = 1.6 min, (M + H) 357.6.

(S) -3- (2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) azepan-2-one (501)

LCMS RT = 1.6 min, (M + H) 341.4.

3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -7,7-dimethylazane-2 -On (504)

LCMS RT = 3.2 min, (M + H) 403.6.

Amines for the compounds are described in J. A. Robl, E. Sieber-McMaster, R. Sulsky Synthetic routes for the generation of 7,7-dialkyl-2-azepinones. Tetrahedron Letters (1996), 37 (50), 8985-8988.

Scheme 42

(a) 3-amino-1-methylpyrrolidin-2-one, DMA, 140 ° C. microwave; (b) LiOH, THF, microwave, 120 ° C. (c) EDCI, HOAt, ⁱ Pr ₂ NEt, DCM-DMF (2: 1).

6- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1,4-oxazepan-5- ON (513)

5-Chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] in DMF (2 mL) A mixture of pyridine (15a) (0.17 g, 0.36 mmol) and (6S) -6-amino-1, 4-oxazanepan-5-one (0.06 g, 0.43 mmol) was prepared using ⁱ Pr ₂ NEt (0.10 mL, 0.57 mmol). Heated to 90 ° C. After 1 hour, the temperature rose to 100 ° C. After 24 hours, the mixture was heated to 140 ° C. for 15 minutes (microwave). The mixture was partitioned between water and EtOAc, and the aqueous layer was extracted twice more with EtOAc. The combined organic phases were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo.

The crude material obtained (0.16 g) was treated with LiOH (1 N solution, 1 mL) in THF (3 mL) overnight. LC-MS showed hydrolysis of the amide with detosylation. The mixture was concentrated in vacuo and purified by preparative HPLC to give semi pure product (23 mg). This material was treated to crystallization conditions without further purification. Fill the flask with crude (0.020 g, 0.051 mmol), EDCI (0.010 g, 0.056 mmol) and HOAt (0.002 g, 0.015 mmol), DCM (1 mL), ⁱ Pr ₂ NEt (0.018 mL, 0.100 mmol) And DMF (0.5 mL) was added. After 1 hour more EDCI (0.7 equiv) was added. After 3.5 hours, the reaction was complete and the mixture was concentrated in vacuo. After purification by preparative HPLC, the TFA salt was removed by filtration through basic resin to give the desired product.

LCMS RT = 1.9 min, (M + H) 377.5.

Starting amines for the compounds are described in J. A. Robl, E. Sieber-McMaster, R. Sulsky Synthetic routes for the generation of 7,7-dialkyl-2-azepinones. Tetrahedron Letters (1996), 37 (50), 8985-8988, according to established methods.

Scheme 43

The following are general methods for converting cyclohexane carboxylic acid (553 or 35a) to carboxamide of the type of compound (43a):

(a) amine, HATU, DMF (b) BOC ₂ O, NH ₄ CO ₃ H, pyridine, DMF; (c) i: amine, HATU, DMF; Ii: 1N LiOH.

(1S, 2S) -2- (2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-ethyl Formation of Cyclohexanecarboxamide 521

(1S, 2S) -2-[[2- (5-chloro-lH-pyrrolo [5,4-b] pyridin-3-yl) -5-fluoro-pyrimidine in DMF (1.0 mL) at room temperature To a mixture of -4-yl] amino] cyclohexane-1-carboxylic acid (553) (0.049 g, 0.126 mmol) and HATU (0.056 g, 0.147 mmol) was added ethylamine (0.189 mL, 0.377 mmol) of 2M solution. The mixture was stirred at room temperature until judged by HPLC that all starting material was converted. After 45 minutes, the mixture was partitioned between aqueous K ₂ CO ₃ and EtOAc, the organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. Preparative HPLC provided the desired product as a TFA salt, which was eluted with MeOH through a basic PSA cartridge and then converted to the parent compound by vacuum concentration (14 mg, 30% yield).

LCMS RT = 2.0 min, (M + H) 417.5.

(1S, 2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N Diethylcyclohexanecarboxamide

LCMS RT = 2.26 min, (M + H) 445.58.

Cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxamide (544) And cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N-dimethylcyclo Formation of Hexane Carboxamide (543)

Cis-2-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl in DMF (5 mL) at room temperature ] Pyridine (0.61 g, 0.62 mL, 7.70 mmol) was added to a mixture of] amino] cyclohexanecarboxylic acid 554 (0.30 g, 0.77 mmol), followed by di-tert-butyl dicarbonate (0.50 g, 2.31 mmol). And NH ₄ CO ₃ H (0.33 g, 4.22 mmol). The mixture was stirred at rt overnight. LC-MS indicated the presence of the desired primary amide as well as the N, N-dimethylamide product. A 1 ml aliquot of the reaction solution was acidified with HOAc and diluted with DMSO. Preparative HPLC chromatography provided both of these products in small amounts.

Primary amide (544), racemic mixture- (8.6 mg): LCMS RT = 1.94 min, (M + H) 389.42.

Dimethylamide (543), racemic mixture- (3.7 mg): LCMS RT = 2.52 min, (M + H) 417.44.

(1R, 2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N Formation of Diethylcyclohexanecarboxamide (518)

(1R, 2S) -2-[[2- [5-chloro-l- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl]-in DMF (1 mL) at room temperature N, N-diethylamine (2M solution 0.138) in a mixture of 5-fluoro-pyrimidin-4-yl] amino] cyclohexane-1-carboxylic acid (0.050 g, 0.092 mmol) and HATU (0.045 g, 0.120 mmol) Ml, 0.280 mmol) was added. When judged by HPLC, the reaction was complete, LiOH in water (0.4 mL of 1M solution, 0.4 mmol) was added. After 6 h, LiOH (1 M 0.4 mL, 0.4 mmol) was added again and the mixture was stirred overnight. The mixture was quenched with saturated aqueous NH ₄ Cl solution. Aqueous K ₂ CO ₃ was added and the mixture was extracted with EtOAc (3 times) and the combined organic phases were washed with saturated aqueous NH ₄ Cl solution, filtered and concentrated in vacuo. Preparative HPLC provided the desired product as a TFA salt, which was converted to HCl salt by treatment with HCl in MeOH and then evaporation of the solvent (12.9 mg, 28% yield).

LCMS RT = 3.3 min, (M + H) 445.6.

(1R, 2S) -2- (2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-ethyl Cyclohexanecarboxamide (519)

LCMS RT = 2.95 min, (M + H) 417.5.

Cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-methylcyclohexanecarbox Amide (539)-Racemic Mixture

LCMS RT = 2.13 min, (M + H) 403.44.

Scheme 44

(a) Pd (PPh ₃ ) ₄ , sodium carbonate, DME / water, reflux (b) meta-chloroperbenzoic acid, dichloromethane, rt. (c) 20a, tetrahydrofuran, 50 ° C. (d) trifluoroacetic acid, dichloromethane, rt. (e) morpholine-4-carbonyl chloride, dimethylformamide, rt (f) sodium methoxide, methanol, rt.

Formation of 5-fluoro-3- [5-fluoro-4- (methylthio) pyrimidin-2-yl] -1-tosyl-1H-pyrrolo [2,3-b] pyridine (44b)

2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol), 5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (44a) (53.0 g, 127.3 mmol) and Na ₂ CO ₃ (40.5 g, 381.9 mmol) ) Was dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd (PPh ₃ ) ₄ (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600 mL). After the obtained suspension was stirred at room temperature for 30 minutes, the precipitate was recovered by filtration, washed with water and acetonitrile and dried at 50 ° C. to 5-fluoro-3- [5-fluoro-4- (methyl 48.2 g of thio) pyrimidin-2-yl] -1-tosyl-1H-pyrrolo [2,3-b] pyridine was obtained as a white solid.

Formation of 5-fluoro-3- [5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl] -1-tosyl-1H-pyrrolo [2,3-b] pyridine (44c)

5-fluoro-3- [5-fluoro-4- (methylthio) pyrimidin-2-yl] -1-tosyl-1H-pyrrolo [2,3-b] pyridine (44b) (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) and partitioned with m-CPBA (27.5 g, 122.6 mmol) while maintaining the temperature below 20 ° C. After the addition was complete, the reaction was stirred at room temperature for 2 hours, then treated with another portion of m-CPBA (1.9 g) and stirred for another hour. The reaction mixture was washed with 12% aqueous K ₂ CO ₃ ( ₂ × 1.0 L), the organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to 5-fluoro-3- [5-fluoro-4- (methyl 50 g of sulfinyl) pyrimidin-2-yl] -1-tosyl-1H-pyrrolo [2,3-b] pyridine was provided as a yellow solid.

Tert-butyl N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine- 3-yl] pyrimidin-4-yl] amino] cyclohexyl] carbamate (44d)

5-fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (44c) ( 5.9 g, 10.5 mmol) and tert-butyl N-[(1R, 3S) -3-aminocyclohexyl] carbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50 ° C. for 6 hours and then cooled to room temperature. Celite was added and the solvent was removed under reduced pressure. Celite-supported residue was purified by silica gel chromatography (20-80% EtOAc / hexane gradient) to give tert-butyl N-[(1R, 3S) -3-[[5-fluoro-2- 3.7 g of [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] carbamate was provided.

(1S, 3R) -N1- [5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] pyrimidine-4 -Yl] cyclohexane-1,3-diamine (44e) formation

Tert-butyl N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine- 3-yl] pyrimidin-4-yl] amino] cyclohexyl] carbamate (44d) (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). . After 5 minutes, the volatiles were evaporated under reduced pressure and the residue obtained was treated with 1N NaOH (75 mL). The precipitate obtained was recovered by filtration, washed with water (3x30 mL) and dried in vacuo (1S, 3R) -N1- [5-fluoro-2- [5-fluoro-1- (p-tol) 2.7 g of rilsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] pyrimidin-4-yl] cyclohexane-1,3-diamine were provided as a white solid.

N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] Formation of pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide (44f)

(1S, 3R) -N1- [5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] pyrimidine-4 -Yl] cyclohexane-1,3-diamine (44e) (2.3 g, 4.6 mmol) was dissolved in DMF (50 mL), morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2) g, 5.6 mL, 32.3 mmol). After 1 h, the resulting solution was diluted with water (400 mL) and stirred for a further 2 h. The precipitate obtained was recovered by filtration, washed with water (3x50 mL) and dried to give the crude product. This material was purified by flash chromatography using EtOAc / DCM 20-100% on 40 g column to give N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1 2.0 g of (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide as white solid It was.

N-[(1R, 3S) -3-[[5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] Formation of amino] cyclohexyl] morpholine-4-carboxamide 706

N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] Pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide (44f) (2.0 g, 3.2 mmol) was suspended in methanol (50 mL) and 25% sodium methoxylated (19.9 mL) in methanol , 92.3 mmol). After stirring for 1 hour, the solvent was evaporated under reduced pressure and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was recovered, dried over Na ₂ S0 ₄ and concentrated to give the crude product as a yellow solid. This material was purified by silica gel chromatography using DCM / MeOH 1-6% on 40 g column. Purified fractions were treated with 2N HCl in ether and concentrated to give N-[(1R, 3S) -3-[[5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] 1.5 g of pyridin-3-yl) pyrimidin-4-yl] amino] cyclohexyl] -morpholine-4-carboxamide was provided as a white solid.

(1S, 3R) -N1- (2-fluoro-5- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) phenyl) cyclohexane-1,3-diamine ( 44e) formation

Tert-butyl (1R, 3S) -3- (2-fluoro-5- (5-fluoro-1-tosyl-1H-pyrrolo- [2,3-b] pyridine in methylene chloride (22 mL) Hydrogen chloride (2.71 mL of 4M solution in 1,4-dioxane, 10.86 mmol) was added to a solution of -3-yl) phenylamino) cyclohexylcarbamate (44d) (0.65 g, 1.09 mmol). The reaction was heated to 50 ° C. and stirred for 6 hours. The mixture was cooled to rt and concentrated in vacuo to yield a yellow solid. The crude residue was purified via silica gel chromatography (25-50% ethyl acetate / hexane gradient). Desired fractions were combined and concentrated in vacuo to prepare 350 mg of compound (44e) as a yellow powder.

1-cyano-N-((1R, 3S) -3- (2-fluoro-5- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) phenylamino) Synthesis of cyclohexyl) cyclopropanecarboxamide (871)

HATU (0.200 g, 0.527 mmol) was added to a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058 g, 0.527 mmol) in THF at room temperature, followed by N, N-diisopropylethylamine (0.334 mL). , 1.91 mmol) was added. The solution was stirred for 10 minutes. Then (1S, 3R) -N1- (2-fluoro-5- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) phenyl) cyclohexane-1,3- Diamine 44e (0.200 g, 0.584 mmol) was added and the solution was stirred at rt for 4 h. The mixture was concentrated in vacuo and purified via silica gel chromatography (30-60% ethyl acetate / hexanes) to afford 80 mg of compound (871) as off-white solid.

Scheme 45

(a) 4-chlorobutanoyl chloride, Et ₃ N, CH ₂ Cl ₂ ; (b) KOtBu, THF; (c) H ₂ , Pd-C, MeOH; (d) 45c, Na ₂ CO ₃ , THF-CH ₃ CN, 135 ° C .; (e) 4M HCl, dioxane-CH ₃ CN.

Formation of Benzyl (1S, 3R) -3- (4-chlorobutaneamido) cyclohexylcarbamate (45a)

To a stirred slurry of benzyl N-[(1S, 3R) -3-aminocyclohexyl] carbamate (18e) (0.97 g, 3.41 mmol) in CH ₂ Cl ₂ (34 mL), Et ₃ N (1.00 mL, 7.15 mmol), then 4-chlorobutanoyl chloride (0.40 mL, 3.58 mmol) was added. After stirring at room temperature, the mixture was diluted with CH ₂ Cl ₂ and washed with 1N HCl (twice), 1N NaOH (twice) and brine. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford 1.07 g of the desired product.

Formation of Benzyl (1S, 3R) -3- (2-oxopyrrolidin-1-yl) cyclohexylcarbamate (45b)

To a slurry of benzyl (1S, 3R) -3- (4-chlorobutanamido) cyclohexylcarbamate (45a) (0.21 g, 0.58 mmol) in THF (8.2 mL) at room temperature tert-butoxylated (0.08 g, 0.69 mmol) was added. After stirring for 25 h at rt, the mixture was quenched with aqueous saturated NH ₄ Cl and extracted with Et ₂ O (3 times). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Flash chromatography (SiO ₂ , 0-100% EtOAc-hexanes, gradient) provided a single fraction (168 mg) consisting of the desired product and a small amount of starting material. This material was immediately treated with deprotection conditions.

Formation of 1-((1R, 3S) -3-aminocyclohexyl) pyrrolidin-2-one (45c)

Benzyl (1S, 3R) -3- (2-oxopyrrolidin-1-yl) cyclohexylcarbamate (45b) (0.165 g, 0.522 mmol) and C-supported Pd (10% wet, in MeOH (15 mL) A degassed solution of Degussa, 0.050 g, 0.024 mmol) was placed under H ₂ atmosphere (balloon). After 105 minutes, TLC (10% MeOH-DCM) showed complete consumption of starting material. H ₂ was removed and the solution was filtered and concentrated in vacuo. The crude product was azeotropic with CH ₃ CN (twice) to remove any residual MeOH and provided the desired product (96 mg): FIA (M + H ⁺ ) 183.27

1-((1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4- Formation of monoamino) cyclohexyl) pyrrolidin-2-one (45d)

5-Chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl)-in THF (2.25 mL) and CH ₃ CN (0.45 mL) Pyrrolo [2,3-b] pyridine (1a) (0.14 g, 0.29 mmol) and 1-((1R, 3S) -3-aminocyclohexyl) pyrrolidine-2-one (45c) (0.10 g, 0.53 mmol) and freshly ground Na ₂ CO ₃ (0.09 g, 0.88 mmol) were heated to 135 ° C. for 30 minutes. The mixture was poured slowly into 15 mL of 1 M HCl and extracted with EtOAc (5 times). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Flash chromatography (SiO ₂ , 0-20% MeOH—CH ₂ Cl ₂ gradient) provided the final product as a viscous residue. Trituration with CH ₃ CN gave an off-white powder (105 mg), which was impure but taken directly to the final deprotection step.

LC / MS R _t = 3.90 min, (M + H) 589.49.

1-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) Formation of Cyclohexyl) pyrrolidin-2-one 956

Partially purified 1-((1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl in CH ₃ CN (5 mL) A mixture of) -5-fluoropyrimidin-4-ylamino) cyclohexyl) pyrrolidin-2-one (45d) (0.105 g, 0.180 mmol) was dissolved in dioxane at 70 ° C. in HCl (4M 2 mL, 8.00). mmol). After 2 hours, the mixture was cooled to room temperature. Then CH ₃ CN was added and the precipitated solid was triturated with additional CH ₃ CN (3 times). Preparative HPLC provided the desired product as HCl salt (35 mg).

 LC / MS RT = 3.15 min, (M + H) 429.53.

Scheme 46

(a) 30% ammonium hydroxide, water, 50 ° C. (b) acetyl chloride, diisopropylethylamine, dichloromethane, rt. (c) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3- b] pyridine, Pd (PPh ₃ ) _4, 2M sodium carbonate, acetonitrile, 130 ° C., microwave

Formation of (1S, 3S) -1- (aminomethyl) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (46b)

2-chloro-5-fluoro-N-[(3S, 5S) -1-oxaspiro [2.5] octan-5-yl] pyrimidin-4-amine (46a) (0.19 g, 0.73 mmol) was dissolved in water ( 75 mL) and treated with 30% ammonium hydroxide (10 mL, 86.0 mmol). The suspension was heated to 50 ° C. for 5 h and then stirred at rt overnight. The volatiles were evaporated under reduced pressure and the residue (1S, 3S) -1- (aminomethyl) -3- (2-chloro-5-fluoro-pyrimidin-4-ylamino) cyclohexanol further purified Used in subsequent steps without.

Formation of N-{[(1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl] methyl} acetamide (46c)

(1S, 3S) -1- (aminomethyl) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (46b) (0.19 g, 0.69 mmol) was converted to dichloromethane (15 ML) and treated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL, 1.38 mmol). After 5 minutes, the reaction mixture was diluted with 1N HCl (30 mL) and the aqueous layer was brought to basic pH by addition of 1N NaOH. The suspension obtained was extracted with dichloromethane (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (20-100% EtOAc / hexane gradient) to give N-{[(1S, 3S) -3 195 mg of-(2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclo-hexyl] methyl} acetamide were obtained as a white effervescent solid.

LCMS RT = 2.82 (M + 1) 317.33.

N-{[(1S, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl] methyl} acetamide (857)

N-{[(1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl] -methyl} -acetamide (46c) (0.2 g, 0.6 mmol) is dissolved in acetonitrile (6 mL) and 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxa Treatment with borol-2-yl) pyrrolo [2,3-b] pyridine (0.5 g, 1.2 mmol) followed by Pd (PPh ₃ ) ₄ (0.07 g, 0.06 mmol). Aqueous 2M sodium carbonate (3.0 mL, 6.1 mmol) was added and the vial was sealed and heated to 130 ° C. for 30 minutes in a microwave. The organic layer was recovered and concentrated in vacuo to afford the crude product, which was dissolved in DMSO and purified by HPLC using 5-70% MeOH / H ₂ O + 6 mM HCl over 15 minutes, after concentration N- { [(1S, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- 75 mg of hydroxycyclohexyl] methyl} acetamide hydrochloride was provided as an off-white crystalline solid.

Scheme 47

(a) tert-butyl N-methyl-N- (2-oxoethyl) carbamate, diisopropylethylamine, THF / EtOH, 70 ° C. (b) HCl / dioxane, THF / MeOH (c) bis ( 4-nitrophenyl) carbonate, diisopropylethylamine, DMF.

Tert-butyl 2-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4- Formation of monoamino) cyclohexyl-amino) ethyl (methyl) carbamate (47b)

(1S, 3R) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclo in THF / EtOH Tert-butyl N-methyl-N- (2-oxoethyl) carbamate (0.10 g, 0.58 mmol) and diiso in a flask containing hexane-1,3-diamine (47a) (0.14 g, 0.39 mmol) Propylethylamine (0.13 mL, 0.77 mmol) was added. The solution was heated to 70 ° C. for 30 minutes. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) was added. The solution was stirred at rt for 12 h. The solution is filtered and the solvent is evaporated under reduced pressure. The residue obtained was purified by HPLC using 5-70% MeOH / H ₂ O + 6 mM HCl to give the desired product.

(1S, 3R) -N1- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N3- (2 Formation of-(methylamino) ethyl) cyclohexane-1,3-diamine (47c)

Tert-butyl 2-((1R, 3S) -3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in dichloromethane / MeOH mixture To a flask containing lopyrimidin-4-ylamino) cyclohexylamino) ethyl (methyl) carbamate (47b) (0.02 g, 0.04 mmol) was added HCl (3.86 mL of 4M solution, 15.44 mmol) in dioxane. . The solution was stirred at rt for 12 h. The solvent was evaporated under reduced pressure and used without further purification.

1-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclo Formation of hexyl) -3-methylimidazolidin-2-one 958

(1S, 3R) -N1- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N3- in DMF Diisopropylethylamine (0.025 mL, 0.144 mmol) and bis (4-nitro) were placed in a flask containing (2- (methylamino) ethyl) cyclohexane-1,3-diamine (47c) (0.020 g, 0.048 mmol). Phenyl) carbonate (0.016 g, 0.053 mmol) was added. The reaction mixture was stirred at rt for 3 h. The residue obtained was purified by HPLC using 5-70% MeOH / H ₂ O + 6 mM HCl to give the desired product.

Scheme 48

(a) 2-methoxyethanamine, HATU, DIEA, CH ₃ CN, DMF

(1R, 3S) -3- (2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N- ( Formation of 2-methoxyethyl) cyclohexanecarboxamide 789

(1R, 3S) -3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclo Hexanecarboxylic acid (HCl salt) (0.05 g, 0.12 mmol), HATU (0.09 g, 0.24 mmol), diisopropylethylamine (0.06 g, 0.47 mmol) and 2-methoxyethanamine (0.04 g, 0.47 mmol) Stir together overnight at room temperature in 1 ml each of DMF and CH ₃ CN. All volatiles were removed by nitrogen stream and heat. The residue was dissolved in methanol and purified by preparative HPLC with 10-90% MeOH / water (HCl modifier) to afford the desired product as an HCl salt.

Scheme 49

(a) methyl (triphenyl) phosphonium bromide, (bis (trimethylsilyl) amino) lithium, THF (b) 3-chloroperoxybenzoic acid, MeOH, H ₂ O (c) methylsulfanyl sodium, THF (d) 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3- b] pyridine, Na ₂ CO ₃ , tetrakis triphenylphosphinepalladium (0), CH ₃ CN (e) 3-chloroperoxybenzoic acid, CH ₂ Cl ₂ (f) NaOMe, MeOH.

Formation of (S) -2-chloro-5-fluoro-N- (3-methylenecyclohexyl) pyrimidin-4-amine (49a)

In a flame-dried flask, (bis (trimethylsilyl) amino) lithium (2.40 mL, 2.40 mmol) in room temperature was added to a suspension of methyl (triphenyl) phosphonium bromide (0.86 g, 2.40 mmol) in THF (100 mL) at room temperature. Added. The reaction mixture was stirred at rt for 1 h. A solution of (S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone (29b) (0.48 g, 2.00 mmol) in 20 mL of THF was added. The reaction was stirred at rt for 2 h. The mixture was poured into brine quenched and the aqueous phase was extracted with EtOAc. The layers were separated and the organic layer was dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-100% EtOAc / hexanes gradient) to give 270 mg of the desired product.

LCMS RT: 3.83 min, (M + 1): 242.2.

Formation of 2-chloro-5-fluoro-N-((3R, 5S) -1-oxaspiro [2.5] octan-5-yl) pyrimidin-4-amine (49b, 49c)

3-chloroperoxybenzoic acid (0.40 g, 1.79 mmol) was added (S) -2-chloro-5-fluoro-N- (3-methylenecyclohexyl) in water (0.6 mL) and MeOH (1.5 mL) at room temperature. To a solution of pyrimidin-4-amine (49a) (0.27 g, 1.12 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ . The organic phase was dried (MgSO ₄ ), filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc / hexane gradient) to give two diastereomers (49b and 49c). Isolated upper (less polar) spot 49b has been moved forward.

LCMS RT = 3.21 (M + l) 258.2.

Formation of (1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (methyl-thiomethyl) cyclohexanol (49d)

2-Chloro-5-fluoro-N-((3R, 5S) -1-oxaspiro [2.5] octan-5-yl) pyrimidin-4-amine (49b) (0.10 g, 0.38 mmol) was diluted with THF ( 2 ml). Sodium methylsulfanyl (0.08 g, 1.15 mmol) was added to the reaction and the mixture was stirred at rt for 3 h. A further 36 mg portion of sodium methylsulfanyl sodium in THF (2 mL) was added and the reaction mixture was stirred at rt overnight. LCMS indicated that the starting material was still present, after which the reaction was warmed to 50 ° C. and stirred for 1 hour. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO ₄ ), filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc / hexane gradient). The product (contaminated with a small amount of starting material) proceeded to the next step without further purification.

LCMS RT = 3.56 (M + 1) 306.2.

(1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Formation of -1- (methylthiomethyl) cyclohexanol (49e)

(1R, 3S) -3- (2-Chloro-5-fluoropyrimidin-4-ylamino) -1- (methylthiomethyl) cyclohexanol (49d) (0.09 g) in CH ₃ CN (4 mL) , 0.28 mmol) in 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Pyrrolo [2,3-b] pyridine (0.14 g, 0.33 mmol) was added, followed by aqueous Na ₂ CO ₃ (0.42 mL, 0.83 mmol) of 2M solution. The reaction was degassed with nitrogen for 15 minutes and tetrakis triphenylphosphinepalladium (0) (0.02 g, 0.01 mmol) was added. The reaction was heated to 140 ° C. for 20 minutes via microwave irradiation. The mixture was cooled to rt and diluted with water / EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc / hexanes gradient).

(1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Formation of -1- (methylsulfonylmethyl) cyclohexanol (49f)

(1R, 3S) -3- (2- (5-Chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluorine in CH ₂ Cl ₂ (2 mL) 3-chloroperoxybenzoic acid (0.034 g, 0.155 mmol) in a cooled (0 ° C.) solution of ropyrimidin-4-ylamino) -1- (methylthiomethyl) cyclohexanol (49e) (0.044 g, 0.077 mmol) ) Was added. After stirring for 1 h at 0 ° C., the mixture was diluted with water and CH ₂ Cl ₂ . The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc / hexanes gradient).

LCMS RT = 4.20 (M + 1) 608.3.

(1R, 3S) -3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- ( Formation of Methylsulfonylmethyl) cyclohexanol 886

(1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine in MeOH (2 mL) To a solution of -4-ylamino) -1- (methylsulfonylmethyl) cyclohexanol (49f) (0.045 g, 0.074 mmol) was added NaOMe (25% w / v 2 mL, 9.255 mmol). After the reaction mixture was stirred for 5 minutes at room temperature, the mixture was quenched by addition of saturated aqueous NH ₄ Cl solution and then diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-10% MeOH / CH ₂ Cl ₂ gradient).

Scheme 50

(a) AlMe ₃ , [Rh ₂ (cod) ₂ Cl ₂ ], (S) -BINAP, THF, 0 ° C. (b) TBSCl, imidazole, DMAP, DMF (c) 3-chloroperoxybenzoic acid, CH ₂ Cl ₂ (d) sodium azide, NH ₄ Cl, MeOH, H ₂ O (e) H ₂ , Pd-C (10%), EtOAc (f) 5-chloro-3- (5-fluoro-4 -(Methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, ⁱ Pr ₂ NEt, microwave, 70 ° C. (g) TBAF, THF

(R) -1-Methylcyclohex-2-enol (50a) Formation

In a flame dried 1000 mL round bottom flask, a mixture of (S) -BINAP (6.2 g, 10.0 mmol) and Rh ₂ (cod) ₂ Cl ₂ (2.1 g, 4.2 mmol) in dry THF (350 mL) was added at room temperature. Stirred for 30 minutes under nitrogen. The homogeneous red reaction mixture was then cooled to 0 ° C. and cyclohex-2-en-1-one (16.0 g, 166.4 mmol) was added, followed by neat trimethylaluminum (12.4 g, 16.5 mL, 166.4). mmol) was added dropwise. The mixture was allowed to warm to room temperature for 30 minutes and then stirred for 1 hour. The reaction was monitored by NMR and the post-treated aliquot showed complete conversion to tertiary alcohol.

When the reaction was complete, its temperature was reduced to 0 ° C. and carefully quenched with saturated aqueous NH ₄ Cl solution (500 mL). The layers are separated, the aqueous phase is further washed with ether (5x100 mL), the combined organic phases are dried (MgSO ₄ ), filtered over a pad of celite and concentrated in vacuo to give a yellowish-brown crude oil. It was. Vacuum distillation (38 ° C., 0.5-1 mm Hg) provided 13.9 g (72%) of amber oil.

Formation of (R) -tert-butyldimethyl (1-methylcyclohex-2-enyloxy) silane (50b)

To a solution of (R) -1-methylcyclohex-2-enol (50a) (1.00 g, 8.91 mmol) in 20 anhydrous DMF at room temperature, 4H-imidazole (1.82 g, 26.74 mmol), tert-butyldimethylchloro Silane (2.02 g, 13.33 mmol) and catalytic amount of 4-dimethylaminopyridine (0.11 g, 0.89 mmol) were added. The resulting mixture was stirred at rt overnight. This was then diluted with ether and washed successively with water, citric acid and water. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. 1.98 g of a colorless crude oil was used directly in the next step without further purification.

Formation of tert-butyldimethyl ((1R, 2R, 6R) -2-methyl-7-oxabicyclo [4.1.0] heptan-2-yloxy) silane (50c)

3-Chlorobenzenecarboperoxoic acid (2.47 g, 11.00 mmol) (R) -tert-butyldimethyl (1-methylcyclohex-2-enyloxy) silane (50b) in 30 mL of anhydrous dichloromethane at room temperature under nitrogen. ) (1.98 g, 8.87 mmol) and a stirred solution of sodium bicarbonate were added in one portion. The resulting mixture was stirred for 20 hours. Then 25% sodium sulfite solution (30 mL) was added and the resulting dibasic mixture was stirred for 15 minutes. The two layers were separated and the aqueous layer was extracted with dichloromethane (2x20 mL). The combined organic phases were washed with aqueous saturated NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% EtOAc-hexane gradient) to give 647 mg of compound (50c).

Formation of (1R, 2R, 3S) -3-azido-1- (tert-butyldimethylsilyloxy) -1-methylcyclo-hexan-2-ol (50d)

Tert-butyl-dimethyl-[[(1R, 5R, 6R) -5-methyl-7-oxabicyclo [4.1.0] heptan-5-yl in methanol (5 mL) and H ₂ O (0.6 mL) ] Oxy] silane (50c) (0.05 g, 2.15 mmol) was added NH ₄ Cl (0.23 g, 0.15 mL, 4.30 mmol) to a stirred solution, followed by sodium azide (0.42 g, 1.26 mL, 6.45 mmol). Was added in fractions. The reaction mixture obtained was warmed to 60 ° C. and stirred for 12 h at which point traces of starting material were identified by TLC-analysis. The reaction mixture was cooled to ambient temperature, quenched with H ₂ O (2 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3 × 15 mL), washed with brine (10 mL) and washed with MgSO ₄ . Dry, filter and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10% ethyl ether / hexane gradient) to give (1R, 2S, 6R) -2-azido-6- [tert-butyl (dimethyl) silyl] oxy-cyclo 254 mg of hexanol (50d) was obtained as a clear oil.

Formation of (1R, 2R, 3S) -3-amino-1- (tert-butyldimethylsilyloxy) -1-methylcyclohexan-2-ol (50e)

A solution of azide (50d) (0.25 g; 0.89 mmol) in 20 mL of ethyl acetate was hydrogenated overnight to degussa palladium (20 mol%) under 1 atmosphere of hydrogen. The reaction mixture was filtered over celite and the celite eluted with 2x10 mL EtOAc. The filtrate was concentrated in vacuo to give 230 mg of oil which was used directly in the next step without further purification.

(1R, 2R, 6S) -2- (tert-butyldimethylsilyloxy) -6- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl Formation of) -5-fluoropyrimidin-4-ylamino) -2-methylcyclohexanol (50f)

(1R, 2R, 6S) -6-amino-2- [tert-butyl (dimethyl) silyl] oxy-2-methyl-cyclohexanol (50e) in THF (8 mL) in a microwave sealed tube vessel ( 0.16 g, 0.62 mmol) in 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3- b] pyridine (1a) (0.29 g, 0.63 mmol) was added followed by N-ethyl-N-isopropyl-propan-2-amine (0.13 mL, 0.74 mmol). The reaction mixture obtained was capped and warmed to 70 ° C. and stirred for 14 h. The reaction mixture was cooled to ambient temperature, water (2 mL) was added and concentrated under reduced pressure to remove THF. The crude product was diluted with ethyl acetate (25 mL) and insoluble matter (sulfone 1a) was removed by filtration. The organic layer was separated, washed with brine (2 × 5 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica-gel plug using 10-30% ethyl acetate / hexanes as eluent to give (1R, 2R, 6S) -2- [tert-butyl (dimethyl) silyl] oxy-6-[[ 2-methyl [5-chloro-1- (p-tolylsulfonyl) -pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyridin-4-yl] amino] cyclohexanol (50f) 350 mg was obtained.

(1R, 2R, 3S) -3- (2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino)- Formation of 1-methylcyclohexane-1, 2-diol 860

(1R, 2R, 6S) -2- [tert-butyl (dimethyl) silyl] oxy-6-[[2-methyl [5-chloro-1- (p-tolylsulfonyl) in THF (2 mL) at room temperature Tetrabutyl in a stirred solution of) -pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyridin-4-yl] amino] cyclohexanol (50f) (0.11 g; 0.16 mmol) Ammonium fluoride (1.5 equiv) was added and the reaction mixture was stirred for 1.5 h, at which point HPLC-analysis showed no starting material, but de-tosylation product was observed with a small amount of desilylation . Additional equivalent of TBAF was added and the reaction mixture was stirred at rt overnight. The reaction mixture was suspended in ethyl acetate (10 mL) and washed with H ₂ O ( ₂ × ₄ mL), saturated aqueous NH ₄ Cl solution (2 mL) and brine (2 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 139 mg of crude residue. The crude residue was purified by reverse phase HPLC (5-95% MeOH / water w / HCl buffer, 15 minutes) to give 15 mg of the desired product 860.

LCMS M + 1 = 392.34

Scheme 51

(a) NaH, BnBr, THF, 60 ° C. (b) 3-chloroperoxybenzoic acid, CH ₂ Cl ₂ , 0 ° C. (c) H ₂ SO ₄ , MeOH (d) TBSCl, imidazole, DMAP, DMF (e ) H ₂ , Pd-C (10%), EtOAc (f) triphenylphosphine, diisopropylazadicarboxylate, diphenylphosphoryl azide, THF (g) H ₂ , Pd-C (10%) , EtOAc (h) 2,4-dichloro-5-fluoropyrimidine, K ₂ CO ₃ , CH ₃ CN / IPA (i) TsOH, MeOH (j) 5-chloro-3- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, aqueous Na ₂ CO ₃ , CH ₃ CN, microwave , 120 ° C. (k) LiOH, H ₂ O / THF, microwave, 120 ° C.

Formation of ((cyclohex-2-enyloxy) methyl) benzene (51a)

A solution of cyclohex-2-en-1-ol (10.0 g, 101.9 mmol) in dry THF (100 mL) was dissolved in sodium hydride (8.0 g, 199.7 mmol) in dry THF (250 mL) maintained at 50 ° C. 60% dispersion in oil) and benzyl bromide. The resulting solution was stirred at 55-60 ° C. for 18 hours. After cooling to ambient temperature, the reaction was quenched by the addition of water and the mixture was diluted with ether (500 mL). The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give an oil, which was treated by short silica plug filtration to be used directly in the next step without further purification. 16.1 g was given.

Formation of racemic cis and trans-1-benzyloxy) -7-oxabicyclo [4.1.0] heptanes (51b and 51c)

A solution of benzyl ether (51a) (16.10 g, 0.89 mol) in 500 mL of CH ₂ Cl ₂ at 0 ° C. was partitioned into 77% m-CPBA (21.08 g; 0.09 mol). The reaction mixture was stirred at 0 ° C. for 2 hours and then at room temperature for 12 hours. When the reaction was complete, it was quenched with sodium thiosulfate (100 mL) and the organic phase was washed with additional 100 mL of sodium thiosulfate followed by aqueous NaHCO ₃ solution, 5% NaOH (200 mL) and finally water. The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give an oil, which was purified by silica gel chromatography (5% → 20% Et ₂ O / hexane) to 11.44 g of trans-epoxide (51b) and 3.95 g of cis-epoxide (51c) was isolated (66:34 ratio).

Formation of racemic 1-benzyloxy-3-methoxycyclohexan-2-ol (51d)

A solution of cis-1-benzyloxy) -7-oxabicyclo [4.1.0] heptane (51c) (2.0 g; 9.8 mmol) in 0.2 N sulfuric acid (9.8 mmol) in 30 mL of anhydrous methanol was stirred at room temperature for 30 minutes. I was. The reaction was diluted with water and extracted with ether. The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo to yield 2.31 g of oil which was used directly in the next step without further purification.

Formation of racemic [1-benzyloxy-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51e)

1-benzyloxy-3-methoxy-cyclohexane-2-ol (51d) (2.31 g, 9.78 mmol) and tert-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66 in 20 anhydrous DMF at room temperature 4H-imidazole (1.997 g, 29.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12 g, 0.98 mmol) were added to the solution of mmol). The resulting mixture was stirred at rt overnight. It was then diluted with ether, washed with water and saturated citric acid aqueous solution and again with water. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. Colorless crude oil was used directly in the next step without further purification.

Formation of racemic [1-hydroxy-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51f)

A solution of racemic [1-benzyloxy-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51e) (3.4 g, 9.7 mmol) was dissolved in ethyl acetate (50 mL), and 45 Hydrogenated with Pd-C 10% under hydrogen of PSI for 1 hour. The reaction mixture was filtered over a nylon / glass fiber filter and concentrated in vacuo to give 2.72 g of the desired product (51f). This material was used directly in the next step without further purification.

Formation of racemic [1-azido-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51 g)

Triphenylphosphine in a solution of racemic [1-hydroxy-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51f) (2.5 g; 9.6 mmol) in 60 mL of dry THF at room temperature. (5.0 g; 19.2 mmol), DIAD (3.9 g; 19.2 mmol) and diphenylphosphoryl azide (5.3 g; 19.2 mmol) were added and the reaction mixture was stirred at rt for 60 h. The solvent was concentrated in vacuo and the oil obtained was purified by silica gel chromatography (10% Et ₂ O-hexane → ether gradient) to give 2.57 g of the desired product (51 g).

Formation of racemic [1-amino-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51h)

A solution of racemic [1-azido-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51 g) (2.57 g; 6.3 mmol) in 20 ml of ethyl acetate was added to the Parr hydrogenation unit for 1 hour. Hydrogenated to Pd-C 10% (5 mol%; degussa) at 45 PSI. The reaction mixture was filtered over nylon and fiberglass filters and concentrated in vacuo to give 2.32 g of the desired product (51h) as a white solid.

Formation of racemic N-((1-2- (tert-butyldimethylsilyloxy) -3-methoxycyclohexyl) -2-chloro-5-fluoropyrimidin-4-amine (51i)

Racemic [1-amino-3-methoxy-2-cyclohexaneoxy] tert-butyl-dimethylsilane (51h) (2.32 g; 6.26 mmol) was added to the flask. To this was added MeCN and IPA (1.5: 1 v / v) in a total volume of 125 ml. To this solution was added dipotassium carbonate (4.32 g, 31.30 mmol) and the mixture was stirred at room temperature for 30 minutes (to remove any water that may be present). 2,4-Dichloro-5-fluoro-pyrimidine (3.14 g, 18.78 mmol) was added to this mixture, and the mixture was stirred at room temperature for 60 hours. The reaction was filtered through celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20-100% ether / hexane gradient) to give 2.27 g of pure racemic compound 51i.

Formation of (1R, 2S, 6R) -2- (2-chloro-5-fluoropyrimidin-4-ylamino) -6-methoxy-cyclohexanol (51j)

Racemic N-((1-2- (tert-butyldimethylsilyloxy) -3-methoxycyclohexyl) -2-chloro-5-fluoropyrimidin-4-amine (51i) in 30 mL MeOH ( P-TsOH (1.73 g; 10.06 mmol) was added to a solution of 1.96 g, 5.03 mmol) The reaction mixture was stirred at rt for 3 h and then concentrated to dryness The residue was dissolved in EtOAc (125 mL) And washed with 1M aqueous potassium carbonate (2 × 50 mL) and then brine The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo, SFC enantiomeric separation (50% EtOH-50% CO). ₂ ; 10 ml / min; 100 bar), 635 mg of chiral alcohol (51j) was obtained as a white solid.

(1R, 2S, 6R) -2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of amino) -6-methoxycyclohexanol (51k)

In a microwave tube, 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [ 2,3-b] pyridine (0.10 g, 0.23 mmol) was added. Acetonitrile (0.61 mL) was added thereto, and the solution was deoxygenated with nitrogen. To the reaction was added (1R, 2S, 6R) -2- (2-chloro-5-fluoropyrimidin-4-ylamino) -6-methoxy-cyclohexanol (51j) (0.04 g, 0.14 mmol) and palladium Catalyst (24 mg) and then aqueous sodium carbonate (0.21 mL 2M solution, 0.41 mmol) were added. The reaction was sealed and heated to 120 ° C. for 15 minutes in a microwave reactor. The reaction was diluted with ethyl acetate (40 mL), filtered through florisil and concentrated in vacuo to afford the crude material as a green solid. This was purified by silica gel chromatography (20-75% EtOAc / hexane gradient). The product obtained was used directly in the next step.

LCMS (M + 1) = 546.35.

(1R, 2S, 6R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -6 Formation of methoxycyclohexanol (831)

Azaindole (51k) (0.050 g; 0.092 mmol) was added to the microwave vial. To this was added 3 ml THF and 0.9 ml 0.8 M LiOH. The vial was sealed and heated to 120 ° C. for 15 minutes in a microwave. When the reaction was complete, it was neutralized with 9 equivalents of 1N HCl (0.704 mL), then saturated aqueous NaHCO ₃ solution was added, the organic phase was separated, loaded onto silica gel for purification, and w / Elution with a 2% MeOH → 12% gradient (4 g column) gave 34.5 mg (91%) of the desired product (831).

Scheme 52

(a) LDA, iodomethane, THF, -78 ° C (b) SOCl ₂ , DMF, CH ₂ Cl ₂ , reflux followed by NH ₄ OH (c) TMSOTf, iodine, Et ₃ N, pentane, CH ₂ Cl ₂ (d) Boc ₂ O, DMAP, CH ₂ Cl ₂ (e) 1,8-diazabicyclo [5.4.0] undec-7-ene, toluene, reflux (f) Cs ₂ CO ₃ , MeOH (g) H ₂ , Pd-C (5%), MeOH, 2 days (h) HCl, MeOH; 2,4-dichloro-5-fluoropyrimidine, ⁱ Pr ₂ NEt, DMF; SFC chiral separation (i) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2 , 3-b] pyridine, Pd (Ph ₃ P) ₄ , Na ₂ CO ₃ , THF / H ₂ O, reflux (j) NaH, MeOH (k) LiOH, H ₂ O / MeOH (l) benzotriazole- 1-yl- [bis (dimethylamino) methylene] oxonium hexafluorophosphate, ⁱ Pr ₂ Net, THF, NH ₄ Cl.

Formation of 1-methylcyclohex-3-ene-1-carboxylic acid (52a)

N-isopropylpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in 50 mL THF. To this solution was added n-butyllithium (174.4 mL of a 2.5M solution in hexane, 436.0 mmol) at -78 ° C. The resulting solution was stirred at −78 ° C. for 30 minutes. Thereafter, cyclohex-3-ene-1-carboxylic acid (25.0 g, 198.2 mmol) was added to the reaction, and the reaction was heated to 60 ° C. for 2 hours. The reaction was cooled to room temperature, iodomethane (29.5 g, 13.0 mL, 208.1 mmol) was added and the reaction stirred overnight, then quenched with 1N HCl to pH <4. The crude product was extracted in CH ₂ Cl ₂ and water. The organic phase was concentrated in vacuo to afford a yellow oil (27 g) which was used without further purification.

MS / RT: 141.09 (M + H) /1.65

Formation of 1-methylcyclohex-3-ene-1-carboxamide (52b)

Thionyl chloride (56.2 mL, 770.4 mmol) and DMF 1 in a solution of 1-methylcyclohex-3-ene-1-carboxylic acid (52a) (54.0 g, 385.2 mmol) dissolved in CH ₂ Cl ₂ (200 mL). Ml was added. The reaction was raised to reflux for 3 hours, then cooled and concentrated in vacuo. The residue was dissolved again in 200 mL of CH ₂ Cl ₂ . Ammonium hydroxide (148.2 mL of 13M solution, 1.9 mol) was slowly added to the reaction. The reaction was stirred overnight. The reaction was extracted in CH ₂ Cl ₂ and water. The organic phase was concentrated in vacuo and purified via flash silica gel chromatography (EtOAc) to afford 25 g of 1-methylcyclohex-3-ene-1-carboxamide.

MS / RT: 139.96 (M + H) /2.66

Formation of 4-iodo-1-methyl-6-azabicyclo [3.2.1] octan-7-one (52c)

A solution of 1-methylcyclohex-3-ene-1-carboxamide (52b) (5.0 g, 35.9 mmol) dissolved in 100 mL of pentane and CH ₂ Cl ₂ was cooled to 0 ° C. and triethylamine (11.0 ML, 79.0 mmol) and trimethylsilyl-triflate (14.3 mL, 79.0 mmol) in sequence. The resulting mixture was stirred at rt for 1 h. The lower layer was removed via a pipette. The upper pentane layer was concentrated in vacuo and the residue obtained was dissolved in THF (100 mL). Iodine (20.1 g, 79.02 mmol) was added to the stirred reaction and the reaction was stirred overnight at room temperature. After quenching with Na ₂ SO ₃ and NaHCO ₃ , the reaction was partitioned between CH ₂ Cl ₂ and water. The organic layers were combined, dried over Na ₂ S0 ₄ and concentrated in vacuo to give a dark yellow oil (9.5 g) which was used without further purification.

MS / RT: 266.06 (M + H) /2.39

Formation of tert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo [3.2.1] octane-6-carboxylate (52d)

DMAP (0.2 g) in a solution of 4-iodo-1-methyl-6-azabicyclo [3.2.1] octan-7-one (52c) (9.5 g, 35.8 mmol) in CH ₂ Cl ₂ (100 mL). , 1.8 mmol), triethylamine (15.0 mL, 107.5 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8 g, 35.8 mmol) were added. The reaction was stirred at rt overnight. The product was extracted in CH ₂ Cl ₂ and water. The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (4: 1 hexanes: EtOAc) to give 7.6 g.

MS / RT: 366.06 (M + H) /3.95

Formation of tert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo [3.2.1] oct-3-ene-6-carboxylate (52e)

To a solution of tert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo [3.2.1] octane-6-carboxylate (52d) (7.6 g, 20.8 mmol) in 100 ml of toluene 1,8-diazabicyclo [5.4.0] undec-7-ene (6.2 mL, 41.6 mmol) was added. The reaction was heated to reflux and stirred overnight. The reaction was concentrated in vacuo and the residue obtained was purified by silica gel chromatography (4: 1 hexanes: EtOAc) to give 4.9 g of the desired product (52e).

MS / RT: 238.14 (M + H) /3.33

Formation of Methyl 5- (tert-butoxycarbonylamino) -1-methylcyclohex-3-enecarboxylate (52f)

Solution of tert-butyl 1-methyl-7-oxo-6-azabicyclo [3.2.1] oct-3-ene-6-carboxylate (52e) (4.93 g, 20.78 mmol) in MeOH (100 mL) Cesium carbonate (13.54 g, 41.56 mmol) was added thereto. The reaction was stirred overnight and then concentrated in vacuo. Cesium salt was precipitated with Et ₂ O and filtered. The ether filtrate was evaporated to give 5.5 g of yellow oil which was used without further purification.

MS / RT: 270.17 (M + H) /3.64

Formation of Methyl 5- (tert-butoxycarbonylamino) -1-methylcyclohexanecarboxylate (52 g)

Methyl 5- (tert-butoxycarbonylamino) -1-methylcyclohex-3-enecarboxylate (52f) (5.59 g, 20.75 mmol) was dissolved in 100 mL of MeOH. To the stirred solution was added 5% carbon supported palladium (1.11 g, 10.38 mmol) and the reaction was stirred for 2 days under a hydrogen balloon. The reaction was filtered through celite and the filtrate was concentrated in vacuo and used without further purification.

MS / RT: 272.24 (M + H) /3.62

Isolation of (1R, 3S) -methyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methyl-cyclohexanecarboxylate (52h)

A stirred solution of methyl 5- (tert-butoxycarbonylamino) -1-methylcyclohexanecarboxylate (52 g) (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred for 1 hour at room temperature, then concentrated to dryness and dissolved again in THF (50 mL). To the reaction mixture was added ⁱ Pr ₂ NEt (10.84 mL, 62.25 mmol) and 2, 4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred under reflux overnight, concentrated in vacuo and the residue obtained was purified by silica gel chromatography (1: 1 hexanes: EtOAc) to give 2.2 g of racemic product as a yellow oil. 300 mg of racemic methyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate was subjected to SFC chiral separation to give 100 mg of the desired product (52h) as a yellow oil. .

MS / RT: 302.16 (M + H) /3.68

(1R, 3S) -Methyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino ) -1-Methylcyclohexanecarboxylate (52i) Formation

(1R, 3S) -Methyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate (52h) in 5 ml THF and 1 ml water in a 25 ml round bottom flask ) (0.061 g, 0.202 mmol), 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- I) Pyrrolo [2,3-b] pyridine (0.096 g, 0.222 mmol) and disodium carbonate (0.064 g, 0.607 mmol) were combined. The reaction mixture was degassed through a nitrogen stream. Tetrakis triphenyl phosphine palladium (0) (0.021 g, 0.202 mmol) was added to the reaction and the reaction was stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4: 1 hexanes: EtOAc) to give 85 mg of the desired product (52i).

MS / RT: 572.33 (M + H) /6.27

(1R, 3S) -Methyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- Formation of Methylcyclohexanecarboxylate (52j)

(1R, 3S) -Methyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- in 10 mL MeOH To a stirred solution of 4-ylamino) -1-methylcyclohexanecarboxylate (52i) (0.085 g, 0.149 mmol) was added NaH (0.004 g, 0.178 mmol) at room temperature. The resulting suspension was stirred for 2 hours and quenched with solid NH ₄ Cl. The mixture was concentrated in vacuo and purified via silica gel chromatography (3: 1 hexanes: EtOAc) to give 55 mg of the desired product (52j).

MS / RT: 418.32 (M + H) /3.30

(1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methyl Cyclohexanecarboxylic acid (826)

(1R, 3S) -Methyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5 dissolved in MeOH (5 mL) and water (1 mL) LiOH (0.004 g, 0.168 mmol) was added to a solution of -fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate (52j) (0.035 g, 0.083 mmol). The reaction was stirred at room temperature for 2 days and then concentrated to dryness. The residue was washed with ethanol. The combined ethanol washes were concentrated in vacuo to afford 30 mg of the desired product as off white solid.

(1R, 3S) -3-[[2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino]- Formation of 1-Methyl-cyclohexanecarboxamide 924

(1R, 3S) -3-[[2- (5-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino]- 1-Methyl-cyclohexanecarboxylic acid 826 (0.050 g, 0.108 mmol), benzotriazol-1-yl- [bis (dimethylamino) methylene] oxonium hexafluorophosphate (0.081 g, 0.216 mmol) and N- Ethyl-N-isopropyl-propan-2-amine (0.075 mL, 0.432 mmol) was combined in 5 mL THF. Ammonia hydrochloride (0.002 g, 0.032 mmol) was then added to the reaction and the reaction was stirred at rt overnight. After concentration under reduced pressure, the mixture was purified by reverse phase HPLC chromatography to give 3.3 mg of the desired product.

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S, 3R) -3-isocyanato-3-methylcyclohexyl Formation of Pyrimidin-4-amine (52m)

(1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl in 10 ml toluene ] Amino] -1-methyl-cyclohexanecarboxylic acid 826 (0.100 g, 0.216 mmol) and N-ethyl-N- in a solution of (azido (phenoxy) phosphoryl) oxybenzene (0.093 mL, 0.432 mmol) 1 ml of isopropyl-propan-2-amine was added. The reaction was heated to reflux overnight. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (EtOAc) to afford 40 mg of the desired product as a white foam.

MS / RT: 401.23 (M + H) /3.89

N-((1R, 3S) -3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino)- Formation of 1-methylcyclohexyl) pyrrolidine-1-carboxamide 926

2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S, 3R) -3 in 3 ml of NMP and 0.5 ml of pyrrolidine A solution of isocyanato-3-methylcyclohexyl) pyrimidin-4-amine (52m) (0.035 g, 0.087 mmol) was heated to 200 ° C. for 30 minutes in a microwave. The reaction was then concentrated in vacuo and purified by reverse phase HPLC chromatography to yield 8.7 mg of the desired product as a tan solid.

Scheme 53

(a) H ₂ , Pd-C, MeOH; (b) Na ₂ CO ₃ , THF-CH ₃ CN, 135 ° C .; (c) NaOMe, MeOH, DCM; (d) NaOH, MeOH, THF.

Formation of (+/-)-2,3-trans-methyl 3-nitrobicyclo [2.2.1] hept-5-ene-2-carboxylate (53a)

The compound is described in Chang, Linda L .; Truong, Quang; Doss, George A .; MacCoss, Malcolm; Lyons, Kathryn; McCauley, Ermengilda; Mumford, Richard; Forrest, Gail; Vincent, Stella; Schmidt, John A .; Hagmann, William K. Bioorg. Med. Chem. Lett. 2007, 17 (3), 597-601, were prepared as a mixture of trans isomers (endo: exo = 84: 16).

Formation of (+/-)-2,3-trans-methyl 3-aminobicyclo [2.2.1] heptane-2-carboxylate (53b)

(+/-)-2,3-trans-methyl 3-nitrobicyclo [2.2.1] hept-5-ene-2-carboxylate (53a) (0.32 g, 1.62 mmol) and Pd-C in MeOH ( 10%) was purged, placed under H ₂ atmosphere (50 PSI) and shaken overnight. The mixture was filtered through celite, concentrated in vacuo and azeotroduced twice with CH ₃ CN to remove traces of MeOH.

¹ H NMR of the crude mixture showed the presence of both endo and exo products (84:16 = endo: exo) and they were used directly in the subsequent reaction without further purification.

(+/-)-2,3-trans-methyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyripy Formation of midin-4-ylamino) bicyclo [2.2.1] heptan-2-carboxylate (53c)

5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo in THF (3.7 mL) and CH ₃ CN (1.2 mL) [ 2,3-b] pyridine (1a) (0.46 g, 1.00 mmol) and (+/-)-trans-methyl 3-aminobicyclo [2.2.1] heptan-2-carboxylate (53b) (0.27 g, 1.60 mmol) (84: 16 = endo: exo) and freshly ground Na ₂ CO ₃ (0.32 g, 2.99 mmol) were heated in a microwave to 120 ° C. for 20 minutes. The reaction mixture was filtered and the solid was washed with Et ₂ O and THF. The organic layer was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (0-40% EtOAc / hexanes, gradient) to separate trans-endo isomers and trans-exo isomers as shown by NMR. A desired product (352 mg) was provided as a mixture that could not be done (endo: exo = 85: 15).

LC / MS R _t = 6.13 min, (M + H) 570.34.

(+/-)-2,3-trans-endo-methyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- 4-ylamino) bicyclo [2.2.1] heptan-2-carboxylate (53d) and (+/-)-2,3-trans-exo-methyl 3- (2- (5-chloro-1H-pi Rolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptan-2-carboxylate (53d)

Trans-endo- and trans-exo-methyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] in MeOH (3 mL) and CH ₂ Cl ₂ (1 mL) NaOMe (25% w) in a solution of pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptan-2-carboxylate (53c) (0.18 g, 0.31 mmol) / v 3 ml, 13.88 mmol) was added. After 90 seconds, the reaction was quenched by the addition of NH ₄ Cl solution (5 mL). The mixture was partitioned between aqueous NH ₄ Cl (saturated) and EtOAc. The aqueous layer was extracted again and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Flash chromatography (SiO ₂ , 0-15% MeOH-DCM, gradient) afforded the desired product as a mixture (white solid): 112 mg. ¹ H NMR indicated that the desired product was present as a mixture of endo isomers and exo isomers (endo: exo = 84: 16), which proceeded to the hydrolysis step.

(+/-)-2,3-trans-exo-methyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- 4-ylamino) bicyclo [2.2.1] heptan-2-carboxylate (53d): Small isomer (exo): LC / MS (method: m117) R _t = 3.17 min, (M + H) 416.27.

(+/-)-2,3-trans-endo-methyl 3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- 4-ylamino) bicyclo [2.2.1] heptan-2-carboxylate (53d): major isomer (endo): LC / MS (method: m117) R _t = 3.49 min, (M + H) 416.27.

(946) (+/-)-2,3-trans-endo-3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyripy Midin-4-ylamino) bicyclo [2.2.1] heptan-2-carboxylic acid and (947) (+/-)-2,3-trans-exo-3- (2- (5-chloro-lH-P Rolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptan-2-carboxylic acid

To a stirred solution of starting methyl ester (53d) (0.076 g, 0.183 mmol) (84:16 = endo: exo) in THF (0.60 mL) and MeOH (0.10 mL) was added NaOH (2M 0.10 mL, 0.201 mmol). It was. The reaction progress was monitored by TLC. After 30 minutes, further NaOH (0.18 mL, 0.37 mmol) and MeOH (0.18 mL) were added. The mixture was stirred for an additional 16 hours at room temperature. The mixture was neutralized with HCl (1M) and concentrated in vacuo. Purification by preparative HPLC provided 52 mg of the major isomer (946) and 11 mg of the minor isomer (947) as hydrochloride.

(946) Major (endo) isomers:

(947) Small (Exo) Isomers:

(1184) (2S, 3S) -3-((2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid

Compound 1184 was prepared in a similar manner as described for compounds 946 and 947 above.

(1070) (2S, 3S) -3-((2- (5-fluoro-1 H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid

Compound 1070 was prepared in a manner similar to that described for compounds 946 and 947 above.

Scheme 54

(a) cyanogen chloride, DMF, 0 ° C., (b) Pd (OH) ₂ / carbon, H ₂ ; 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, ⁱ Pr ₂ NEt / THF 45 ° C., (c) Na / MeOH, (d) (n-Bu) ₂ SnO, TMSN ₃ , toluene, 110 ° C.

Formation of benzyl (1S, 3R) -3-cyanocyclohexylcarbamate (54a)

A suspension of benzyl N-[(1S, 3R) -3-carbamoylcyclohexyl] carbamate (18d) (0.69 g, 2.50 mmol) in DMF (10 mL) at 0 ° C. was added 2,4,6-trichloro- Treated with 1,3,5-triazine (0.61 g, 3.29 mmol) and stirred while slowly warming to room temperature. After 20 minutes, the solution turned gold. After 1 hour, a precipitate formed. After further stirring for 3 hours, it was quenched with ice water (100 mL), extracted with CH ₂ Cl ₂ ( ₂ × 125 mL) and washed with 1N HCl (100 mL). The organic layer was concentrated in vacuo to give 730 mg of residue, which was purified using a pad of silica gel (45 mL) using 30% EtOAc / hexane as eluent to give 621 mg of a white solid after vacuum drying.

(1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Preparation of Cyclohexanecarbonitrile (54b)

Benzyl N-[(1S, 3R) -3-cyanocyclohexyl] carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and 20% Perlman's catalyst (50% wet weight) Treated with 0.13 g. The suspension was degassed with hydrogen for 2 minutes and then placed under fixed hydrogen atmosphere. After 135 minutes, TLC showed no starting material remained. The suspension was filtered through celite, washed with THF, degassed with nitrogen, then ⁱ Pr ₂ NEt (0.21 mL, 1.23 mmol) and 5-chloro-3- (5-fluoro-4- (methylsulfinyl) ) Pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (1a) (0.48 g, 1.02 mmol) was added. The mixture was stirred at 45 ° C. overnight, then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using a 0-60% EtOAc / hexanes gradient to give 293 mg of a white solid.

(1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbonitrile Preparation of 54c

(1R, 3S) -3-[[2- [5-Chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine- 4-yl] amino] cyclohexanecarbonitrile (54b) (0.29 g, 0.55 mmol) was suspended in MeOH (15 mL), sodium metal was added and the mixture was heated to 45 ° C. Sodium was dissolved before the compound. The mixture was stirred until complete by TLC and LCMS. After concentration to reduce the volume, it was quenched with a 1: 1 mixture of saturated aqueous NH ₄ Cl: water (1 mL) and then concentrated to dryness. The residue was diluted with EtOAc and washed with water and brine. The organic layer was concentrated in vacuo to afford 0.3 g of a yellow solid, which was adsorbed onto silica-gel and gradient using 0%% OH: DCM as eluent using a 40 g esco column (0-25% / 6 min, 4 min hold; 25-50% / 4 min, 9 min hold) to give 146 mg of a white solid.

LCMS (10-90% MeOH: Water + Formic Acid). LCMS RT 4.01 ES + 371, ES-369.

(1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbox Preparation of Amide 847

(1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbonitrile The sample of was treated with 4N HCl / dioxane and heated to 78 ° C. overnight. After concentrated to dryness, quenched with aqueous saturated sodium bicarbonate and CH ₂ Cl ₂ was added to give a slurry. Filtered and extracted with CH ₂ Cl ₂ . The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give 189 mg of an orange residue, which was purified by silica gel chromatography (0-10% MeOH: CH ₂ Cl ₂ gradient) to give 9.9 mg of solid. .

LCMS (10-90% MeOH: Water + Formic Acid): RT 3.79 min ES + 389.

N-((1S, 3R) -3- (1H-tetrazol-5-yl) cyclohexyl) -2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl)- Preparation of 5-fluoropyrimidin-4-amine (855)

Dibutyl (oxo) tin (0.016 g, 0.064 mmol) in toluene (3 mL) and (1R, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridine- 3-yl) -5-fluoro-pyrimidin-4-yl] amino] cyclohexane-carbonitrile (54c) (0.043 g, 0.107 mmol) was suspended in azido (trimethyl) silane (0.200 mL, 1.507 mmol). Treated with. The mixture was heated to 120 ° C. overnight in a sealed tube. The mixture was absorbed on silica-gel and purified by silica gel chromatography (25-50% gradient of 20% MeOH: DCM with 0.5% AcOH modifier). The combined fractions were concentrated to dryness to afford a residue, which was triturated with ether and then vacuum dried at 45 ° C. to give 44 mg of a yellow solid.

Scheme 55

(a) hydroxylamine-HCl, EtOH; (b) 5-ethyl-2-methyl-pyridinium borane, HCl, MeOH; (c) N- (oxomethylene) carbamoyl chloride, THF; (d) NaOMe, MeOH.

(S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) cyclo Formation of hexanone oxime 55a

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro in EtOH (8.2 mL) To a solution of -pyrimidin-4-yl] amino] cyclohexanone (0.41 g, 0.81 mmol) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at rt overnight. The mixture was then warmed to 70 ° C. for 15 minutes. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (twice) and filtered through a SiO ₂ plug. The residue obtained was azeotropic with CH ₃ CN (twice) to give an off-white powder that was used without further purification.

LC / MS (Method: m120) R _t = 3.90 min, (M + H) 529.44.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S, 3R) -3- (hydroxyamino) Cyclohexyl) pyrimidin-4-amine (55c) and 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N- ( (1S, 3S) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine (55b):

(S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 in MeOH (10 mL) -Ethylamino) cyclohexanone oxime (0.20 g, 0.38 mmol) and HCl (6 M 0.19 mL, 1.134 mmol) in 5-ethyl-2-methyl-pyridinium borane (0.12 mL, 0.76 mmol) at room temperature Was added. After 30 minutes, the reaction was quenched with NaHCO ₃ . The mixture was extracted successively with Et ₂ O, EtOAc, CH ₂ Cl ₂ and EtOAc. Each organic portion was washed with brine and the combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Flash chromatography (SiO ₂ , 20-100% EtOAc-hexanes) provided the cis-4 (74 mg) isomer and trans-3 (64 mg) isomer.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S, 3S) -3- (hydroxyamino) Cyclohexyl) pyrimidin-4-amine (stereoisomer-3)

LC / MS RT = 3.64 min, (M + H) 531.47.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S, 3R) -3- (hydroxyamino) Cyclohexyl) pyrimidin-4-amine (stereoisomer-4)

LC / MS RT = 3.67 min, (M + H) 531.47.

2-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl-amino) Cyclohexyl) -1,2,4-oxadiazolidine-3,5-dione (796)

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-N-((1S, 3R in THF (2 mL) at 0 ° C. To a solution of) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine (55b) (0.072 g, 0.136 mmol) was added N- (oxomethylene) carbamoyl chloride (0.014 mL, 0.176 mmol). . A white solid formed immediately. The slurry was shaken and sonicated to produce a uniform suspension / slurry. Thereafter, CH ₂ Cl ₂ (1 mL) was added to aid in solvation of the slurry. After 135 minutes, the mixture was treated with NaOMe (2 mL, 25% w / v). After 2 minutes, the mixture was quenched with saturated NH ₄ Cl and acidified with 1M HCl. The mixture was extracted with EtOAc (3 times) and the combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Preparative HPLC provided the desired product (25 mg).

LC / MS RT = 3.12 min, (M + H) 446.45.

2-((1S, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclo Hexyl) -1,2,4-oxadiazolidine-3,5-dione (798)

LC / MS RT = 3.37 min, (M + H) 446.34.

Scheme 56

(a) paraformaldehyde, methoxyphosphonoyloxymethane, 4A body, toluene, 90 ° C, (b) NaOMe, MeOH.

(S) -dimethyl (3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Formation of Piperidin-1-yl) methylphosphonate 56a

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [5,4-b] pyridin-3-yl] -5-fluoro-N-[(3S) -3-py in anhydrous toluene To a solution of ferridyl] pyrimidin-4-amine (1c) (2.00 g, 3.99 mmol) was added 4 'molecular sieve and methoxyphosphonoyloxymethane (0.97 g, 0.81 mL, 8.78 mmol). Paraformaldehyde (0.90 g, 9.98 mmol) was added in fractions with stirring under nitrogen. The mixture was heated to 90 ° C. for 90 minutes. The reaction was cooled to rt, diluted with saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by silica gel chromatography using a 0-10% MeOH / CH ₂ Cl ₂ gradient to give 2.0 g of the desired product.

LCMS RT = 4.47 (M + H) 623.3.

(S) -Dimethyl (3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine- Formation of 1-yl) methylphosphonate 690

2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -N-[(3S) -1- (dimethoxy in MeOH (40 mL) Sodium methanolate (25% w / v 20 mL, 92.55 mmol) in a solution of phosphorylmethyl) -3-piperidyl] -5-fluoro-pyrimidin-4-amine (56a) (1.00 g, 1.61 mmol) ) Was added and the reaction mixture was stirred at room temperature for 30 minutes. All volatiles were removed at reduced pressure and the residue obtained was diluted with saturated aqueous NH ₄ Cl solution and extracted twice with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography using a 0-10% MeOH: CH ₂ Cl ₂ gradient to give 270 mg of a white solid.

Scheme 57

(a) pyrazole-1-carboxamidine hydrochloride, ⁱ Pr ₂ NEt, 4A body, toluene, 90 ° C. (b) NaOMe, MeOH.

(S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) pi Formation of Ferridine-1-carboximideamide (57a)

Pyrazole-1-carboxamidine hydrochloride (0.12 g, 0.80 mmol) and 2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] in DMF (0.9 mL) ^I Pr ₂ NEt (0.14) in a solution of pyridin-3-yl] -5-fluoro-N-[(3S) -3-piperidyl] pyrimidin-4-amine (1c) (0.40 g, 0.80 mmol) Ml, 0.80 mmol) was added. The reaction mixture was stirred at rt for 4 h. The mixture was diluted with water, filtered, washed with more water and then with ether. The filtrate was concentrated in vacuo. The residue obtained was purified by silica gel chromatography using a 5-20% MeOH / CH ₂ Cl ₂ gradient (product eluted with 20% MeOH) to afford 190 mg of the desired product.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1- Formation of Carboximideamide 881

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro in MeOH (5 mL) To a solution of pyrimidin-4-yl] amino] piperidine-1-carboxamidine (57b) (0.18 g, 0.32 mmol) add sodium methanolate (25% w / v 3 mL, 13.88 mmol) And the reaction was stirred at room temperature. After 5 minutes, the mixture was concentrated in vacuo to yield a pale yellow solid. The crude residue was purified via preparative HPLC (MeOH / 1% aqueous HCl) to afford the desired product.

Scheme 58

(a) 3-bromoprop-1-ene, Zn dust, DMF (b) 5-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, Pd (Ph ₃ P) ₄ , Na ₂ CO ₃ , acetonitrile, water, 120 ° C., microwave, (c) OsO ₄ , Pyridine, 4-methylmorpholine-N-oxide, tert-butanol, water, THF, 120 ° C. (d) NaOMe, MeOH.

Formation of (3S) -1-allyl-3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (58a)

(3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanone (29b) (0.60 g, 2.46 mmol) and 3-bromoprop-1- in DMF Zn dust (0.32 g, 4.92 mmol) was added to a solution of yen (0.43 mL, 4.92 mmol). The reaction was stirred at rt for 3 days. The mixture was diluted with saturated aqueous NH ₄ Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using a 0-50% EtOAc / hexanes gradient to give 553 mg of the desired product (58a) as an oil.

LC / MS-two peaks corresponding to two diastereomeric products: 286.4 (M + H), RT = 3.41 and 3.78.

(1R, 3S) -1-allyl-3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 -Ylamino) cyclohexanol and (1R, 3S) -1-allyl-3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl)- Formation of 5-fluoropyrimidin-4-ylamino) cyclohexanol (58b and 58c)

In a microwave tube, 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5- in acetonitrile (12 mL) and Na ₂ CO ₃ (1.65 mL, 3.31 mmol) in 2M aqueous solution Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (0.57 g, 1.32 mmol) and (3S) -1-allyl-3-[(2- Chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanol (58a) (0.32 g, 1.10 mmol) was added. The mixture was deoxygenated with nitrogen for 15 minutes. Tetrakis triphenyl phosphine palladium (0) (0.03 g, 0.02 mmol) was added to the mixture. The reaction was sealed and heated to 120 ° C. for 20 minutes. The mixture was diluted with brine and extracted twice with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography using a 10-60% EtOAc / hexanes gradient to give two diastereomers:

Diastereomer 1 (spot more polar-58c): LCMS RT = 4.45 min, (M + H) = 556.48

Diastereomer 2 (less polar spot-58b): LCMS RT = 4.48 min, (M + H) = 556.48

3-((1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4- Formation of monoamino) -1-hydroxycyclohexyl) propane-1,2-diol (58d)

(3S) -1-allyl-3-[[2- [5-chloro-1- (p-tolylsul) in 2-methyl-2-propanol (9.23 mL), THF (3.69 mL) and water (1.85 mL) Pyridine (pyrodine [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] cyclohexanol (58c) (0.30 g, 0.54 mmol) in a solution of pyridine ( 0.09 mL, 1.08 mmol) and osmium tetraoxide (2.5% w / v 0.27 mL, 0.03 mmol) and 4-methylmorpholine N-oxide (0.07 mL, 0.65 mmol) were added. The reaction mixture was heated to 80 ° C. for 20 hours. After cooling to room temperature, the mixture was diluted with saturated aqueous sodium bisulfate solution and extracted twice with 20% isopropanol / CH ₂ Cl ₂ . The combined organic phases were washed with additional saturated aqueous sodium bisulfate solution, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography using a 5-10% MeOH / CH ₂ Cl ₂ gradient to give 175 mg of the desired product (58d) as a racemic mixture.

3-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino)- Formation of 1-hydroxycyclohexyl) propane-1,2-diol 718

3-((1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro in MeOH (5 mL) To a solution of ropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propane-1,2-diol (58d) (0.11 g, 0.18 mmol), 2 ml of sodium methanolate (25% w / v solution, 9.26 mmol) was added and the reaction mixture was stirred at room temperature. After 20 minutes, the reaction mixture was diluted with saturated aqueous NH ₄ Cl solution and extracted twice with 20% IPA / CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification via silica gel chromatography using a 5-20% MeOH: CH ₂ Cl ₂ gradient gave 56 mg of a white solid.

Scheme 59

(a) benzyloxyphosphonoyloxymethylbenzene, triethylamine, 95 ° C., microwave, (b) NaOMe, MeOH.

Dibenzyl (1S, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Amino) -1-hydroxycyclohexylphosphonate and dibenzyl (1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3- Formation of I) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexylphosphonate (59a and 59b)

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine in benzyloxyphosphonoyloxymethylbenzene (2.58 mL, 11.67 mmol) Triethylamine (0.22 mL, 1.56 mmol) was added to a solution of -3-yl] -5-fluoro-pyrimidin-4-yl] amino] cyclohexanone (28a) (0.40 g, 0.78 mmol). The reaction mixture was heated to 95 ° C. for 15 hours. The mixture was diluted with saturated aqueous NaHC0 ₃ solution, extracted with EtOAc and washed again with saturated aqueous NaHC0 ₃ solution. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to yield a white solid. The crude product was purified via silica gel chromatography using a 0-10% MeOH / CH ₂ Cl ₂ gradient to give 518 mg of a mixture of diastereomers containing some benzyloxyphosphonoylmethylbenzene. The mixture was used in the next step without further purification.

LCMS RT = 4.6 (M + H) 776.32.

Dimethyl (1S, 3S) -3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- Hydroxycyclohexylphosphonate and dimethyl (1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine- Formation of 4-ylamino) -1-hydroxycyclohexylphosphonate (741, 742)

(1R, 3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyri in MeOH Midin-4-yl] amino] -1-dibenzyloxyphosphoryl-cyclohexanol and (1S, 3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [ To a solution of 2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] -1-dibenzyloxy was added sodium methanolate and the reaction was stirred at room temperature. After 15 minutes, the reaction mixture was diluted with saturated aqueous NH ₄ Cl solution and extracted twice with 20% IPA / CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by silica gel chromatography using 0-5% MeOH: CH ₂ Cl ₂ to elute impurities and 5% -10% to elute the bottom two spots.

Diastereomer 1 [741]:

Diastereomer 2 [742]:

Scheme 60

Formation of ethyl 2-((1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxy-cyclohexyl) ethanoate (60a)

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N ₂ . After addition of THF (8.0 mL), a solution of chloro (trimethyl) silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added, stirred at room temperature for 15 minutes and then heated to reflux. After cooling to room temperature, a solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture. Thereafter, a solution of (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanone (29b) (2.00 g, 8.21 mmol) in THF (6.0 mL) was removed. Added. The mixture was refluxed for 2 hours and then concentrated in vacuo. EtOAc and saturated aqueous NaHCO ₃ solution were added and the product was extracted with additional EtOAc (3 times), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (hexane: EtOAc) separated the two products. The first peak was compound (60a) (2.05 g, 6.18 mmol, 75%). LCMS +: 332.20, 3.57 min (10-90% MeOH, 3/5 grad / run, formic acid).

Ethyl 2-((1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine-4 Formation of -ylamino) -1-hydroxycyclohexyl) ethanoate (60c)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in acetonitrile (6.0 mL) To a solution of pyrrolo [2,3-b] pyridine (0.31 g, 0.72 mmol) ethyl 2-((1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino)- 1-hydroxycyclohexyl) ethanoate 60a (0.20 g, 0.60 mmol) was added and degassed under N ₂ . Na ₂ CO ₃ (2M 0.90 mL, 1.81 mmol) was added followed by Pd (PPh ₃ ) ₄ (0.10 g, 0.09 mmol). The reaction was sealed and microwave irradiated at 120 ° C. for 30 minutes. The material was concentrated under reduced pressure, then diluted with EtOAc and aqueous saturated NaHCO ₃ , then extracted with additional EtOAc (3 times), dried (Na ₂ SO ₄ ) and concentrated in vacuo. This material was diluted with DCM and 217 mg of product (60c) was obtained by silica gel chromatography (hexane: EtOAc).

LC MS +: 602.49, 4.62 min (10-90% MeOH, 3/5 grad / run, formic acid).

2-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) Formation of -1-hydroxycyclohexyl) ethanic acid (60d)

Ethyl 2-((1R, 3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5- in THF (5.0 mL) To a solution of fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) ethanoate (60c) (0.14 g, 0.22 mmol) was added LiOH (1.12 mL of 1 M aqueous solution, 1.12 mmol). The reaction was microwave irradiated at 130 ° C. for 30 min, neutralized with HCl (2M 0.56 mL, 1.12 mmol), concentrated under reduced pressure, diluted with toluene and concentrated (twice) to give compound (60d) without further purification. Obtained.

LC MS +: 420.30, 3.05 min (10-90% MeOH, 3/5 grad / run, formic acid).

2-((1R, 3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) Formation of -1-hydroxycyclohexyl) -N-methylethaneamide (751)

2-((1R, 3S) -3- (2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5 in MeCN (1.6 mL) and DMF (1.6 mL) In a solution of -fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) ethanolic acid (60d) (0.032 g, 0.076 mmol), HATU (0.058 g, 0.152 mmol), methanamine (0.154 mL of 2M solution) , 0.305 mmol) and ⁱ Pr ₂ NEt (0.053 mL, 0.305 mmol) were added. The reaction was heated to 60 ° C. overnight and then concentrated in vacuo. The residue obtained was purified by reverse phase HPLC (water / HCl: MeOH). Pure fractions were combined and concentrated in vacuo to yield 29 mg of compound (751) as an HCl salt.

Scheme 61

Formation of ethyl 2-((1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propanoate (61b) (step A):

Zinc dust (1.21 g, 18.47 mmol, 3 equiv) was heated with a heat gun under N ₂ . After addition of THF (6.0 mL), a solution of chloro (trimethyl) silane (0.47 mL, 3.69 mmol) in THF (6.0 mL) was added, stirred at room temperature for 15 minutes, and then heated to reflux and cooled. Ethyl 2-bromopropanoate (3.34 g, 18.47 mmol) and (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexane in THF (6.0 mL) A solution of ON 61a (1.50 g, 6.16 mmol) was added slowly to the zinc mixture. The mixture was refluxed for 2 hours and then concentrated in vacuo. EtOAc and aqueous saturated NaHCO ₃ were added and the product was extracted with EtOAc (3 times), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (hexane: EtOAc) separated the two products. The first product eluted in 20-35% ethyl acetate and the second eluted at 35-40%. Fractions of the second product were concentrated in vacuo to give 760 mg of compound 61b.

LCMS +: 346.23, 3.35 min (10-90% MeOH, 3/5 grad / run, formic acid).

Ethyl 2-((1S, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine- Formation of 4-ylamino) -1-hydroxycyclohexyl) propanoate (61c)

5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in acetonitrile (3.6 mL) In a solution of pyrrolo [2,3-b] pyridine (0.21 g, 0.38 mmol) ethyl 2-((1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propanoate (61b) (0.12 g, 0.35 mmol) was added and degassed under N ₂ . Na ₂ CO ₃ (0.52 mL of 2M aqueous solution, 1.041 mmol) was added followed by Pd (PPh ₃ ) ₄ (0.06 g, 0.052 mmol). The reaction was sealed and heated to 120 ° C. for 30 minutes in microwave. The material was concentrated under reduced pressure, then diluted with EtOAc and aqueous saturated NaHCO ₃ and then extracted with additional EtOAc (3 times). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated in vacuo. This material was diluted with CH ₂ Cl ₂ and silica gel chromatography (hexane: EtOAc) gave 200 mg of compound (61c).

LCMS +: 600.35, 4.22 min (10-90% MeOH, 3/5 grad / run, formic acid).

2-((1S, 3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) Formation of -1-hydroxycyclohexyl) propanoic acid (61d)

Ethyl 2-((1S, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3 in THF (3 mL) To a solution of -yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) propanoate (61c) (0.20 g, 0.33 mmol) was added LiOH (3 mL of 1M aqueous solution, 3.0 mmol). The reaction was stirred at room temperature over 2 days, then neutralized with HCl (2M 1.5 mL, 3.0 mmol), concentrated to dryness, diluted with toluene and concentrated again (twice) to give the compound used without further purification ( 61d).

LCMS +: 418.32, 2.62 min (10-90% MeOH, 3/5 grad / run, formic acid).

(4R, 5S, 7S) -7- (5-Fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino)- Formation of 4-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (967)

2-[(1S, 3S) -3-[[5-fluoro-2- (5-fluoro-1H-pyrrolo [2,2] in toluene (5 mL) and triethylamine (0.048 mL, 0.341 mmol) 3-b] pyridin-3-yl) pyrimidin-4-yl] amino] -1-hydroxycyclohexyl] propanoic acid (61d) (0.095 g, 0.228 mmol) (azido (phenoxy) Phosphoryl) oxybenzene (0.059 mL, 0.273 mmol) was added. The reaction was heated to 120 ° C. overnight in a closed tube. The reaction was concentrated in vacuo and purified by reverse phase HPLC (water / HCl: MeOH) to separate diastereomers. To remove traces of residual starting material, the first peak was diluted with MeOH (1 mL) and passed through a PL-HCO3 MP SPE cartridge to give a free base. This material was then chlorided (HCl in water) and concentrated in vacuo to afford 16 mg of compound (967) as an HCl salt.

Scheme 62

Formation of (S) -ethyl 2- (3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylidene) ethanoate 62a

Ethyl 2 in a solution of (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanone (29b) (2.00 g, 8.21 mmol) in toluene (40 mL) -Triphenylphosphoranylideneacetate (4.29 g, 12.31 mmol) was added. The reaction was refluxed overnight, then concentrated in vacuo and purified by silica gel chromatography (hexane: EtOAc). The desired product eluted in 15% ethyl acetate. The clear fractions were combined and concentrated to give 2.57 g of 62a.

LCMS +: 314.18, 3.75 min (10-90% MeOH, 3/5 grad / run, formic acid).

Formation of ethyl 2-((3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (nitromethyl) cyclohexyl) ethanoate (62b)

(S) -ethyl 2- (3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylidene) ethanoate 62a (2.58) in nitromethane (44.53 mL, 822.3 mmol) g, 8.22 mmol) was added 1,1,3,3-tetramethylguanidine (1.55 mL, 12.33 mmol). The reaction was refluxed overnight, then concentrated in vacuo, purified by silica gel chromatography (hexane: EtOAc), and then purified by second chromatography (CH ₂ Cl ₂ : 20% MeOH / CH ₂ Cl ₂ ). Fractions containing pure product were combined and concentrated to give 1.8 g of 62b.

LCMS +: 375.32, 3.64 min (10-90% MeOH, 3/5 grad / run, formic acid).

Formation of (7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one (62c)

Ethyl 2-((3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (nitromethyl) cyclohexyl) ethanoate (62b) in MeOH (20 mL) ( Raney nickel (0.03 g, 0.43 mmol) was added to a solution of 1.60 g, 4.27 mmol). The reaction was shaken at 40 psi H ₂ overnight in a Parr apparatus. The reaction was filtered, concentrated in vacuo and purified by silica gel chromatography (CH ₂ Cl ₂ : 20% MeOH / CH ₂ Cl ₂ ) to give 155 mg of 62c.

LCMS +: 299.13, 2.87 min (10-90% MeOH, 3/5 grad / run, formic acid).

(7S) -7- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -2 Formation of azaspiro [4.5] decan-3-one (62d)

5-Chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in acetonitrile (1.6 mL) To a solution of pyrrolo [2,3-b] pyridine (0.083 g, 0.195 mmol) (7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5 ] Decane-3-one (62c) (0.053 g, 0.177 mmol) was added and degassed under N ₂ . Aqueous Na ₂ CO ₃ (0.266 mL 2M solution, 0.5320 mmol) was added followed by Pd (PPh ₃ ) ₄ (0.031 g, 0.027 mmol). The reaction was sealed and heated to 120 ° C. in microwave for 30 minutes and then concentrated in vacuo. This material was diluted with CH ₂ Cl _2, and hexane: EtOAc, then was carried out by silica gel chromatography using a gradient of _{20% MeOH / CH 2 Cl 2} . Pure fractions were combined and concentrated to give 91 mg of compound 62d.

LCMS +: 569.26, 4.20 min (10-90% MeOH, 3/5 grad / run, formic acid).

(7S) -7- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -2-azaspiro [ 4.5] formation of decan-3-one (969)

(7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one (62d) (0.091 g, 0.159 in MeOH (2 mL) To the solution of mmol) was added NaOMe (25% w / v 2 mL, 9.255 mmol). The reaction was stirred for 0.5 h and then concentrated in vacuo. This material was purified by reverse phase HPLC (water / HCl: MeOH) to give a mixture of diastereomers. Fractions containing pure product were combined and concentrated to yield 50 mg of HCl salt of compound 969.

Scheme 63

Formation of ethyl 2-((1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) ethanoate (63a)

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N ₂ . After addition of THF (8.0 mL), a solution of chloro (trimethyl) silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added, stirred at room temperature for 15 minutes, and then heated to reflux and cooled. A solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture, followed by (3S) -3-[(2-chloro-5- in THF (6.0 mL). A solution of fluoro-pyrimidin-4-yl) amino] cyclohexanone (29b) (2.00 g, 8.21 mmol) was added. The mixture was refluxed for 2 hours and then concentrated in vacuo. EtOAc and saturated aqueous NaHCO ₃ solution were added and the product was extracted with additional EtOAc (3 times), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (hexane: EtOAc) separated the two products. Fractions containing the second (small amount) peak were combined and concentrated to give 470 mg of compound (63a).

LCMS +: 332.13, 3.2 min (10-90% MeOH, 3/5 grad / run, formic acid).

Formation of (5S, 7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-oxa-3-azaspiro [4.5] decan-2-one (63b)

Ethyl 2-((1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) ethanoate (63a) in anhydrous MeOH (6 mL) To a solution of (0.40 g, 1.20 mmol) was added hydrazine (0.75 mL, 23.4 mmol). The reaction was stirred at rt overnight and then concentrated under N ₂ stream. The reaction was diluted with HCl (20 mL of 1 M solution, 20 mmol) until acidic and cooled to 0-5 ° C. Then NaNO ₂ (1.44 mL of 1M solution, 1.44 mmol) was added slowly. Benzene: CHCl ₃ (1: 1) (20 mL) was added and the mixture was stirred. The organic layer was separated and slowly added to refluxed benzene. It was refluxed for 0.5 h and then concentrated. Silica gel chromatography (CH ₂ Cl ₂ : 20% MeOH / CH ₂ Cl ₂ ) gave 92 mg of pure product (63b).

LCMS +: 301.15, 2.76 min (10-90% MeOH, 3/5 grad / run, formic acid).

Of (5S, 7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (63c) formation

(5S, 9S) -9-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] -1-oxa-3-azaspiro [4.5] decane-2- in DMF (8.2 mL) The solution of on (63b) (0.049 g, 0.163 mmol) was cooled to 0 ° C. NaH (0.010 mg, 0.244 mmol) was added followed by MeI (0.011 mL, 0.179 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and concentrated in vacuo. NaHCO ₃ saturated aqueous solution was added and the product was extracted with EtOAc (3 times), washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. This material was purified using silica gel chromatography (CH ₂ Cl ₂ : 20% MeOH / CH ₂ Cl ₂ ) to give compound 63b.

LCMS +: 315.19, 2.83 min (10-90% MeOH, 3/5 grad / run, formic acid).

(5S, 7S) -7- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) Formation of -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (63d)

5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in acetonitrile (0.570 mL) To a solution of pyrrolo [2,3-b] pyridine (0.031 g, 0.0724 mmol) in (5S, 7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -3-methyl- 1-oxa-3-azaspiro [4.5] decan-2-one (63c) (0.019 g, 0.060 mmol) was added and degassed under N ₂ . Na ₂ CO ₃ (2M 0.091 mL, 0.1810 mmol) was added followed by Pd (PPh ₃ ) ₄ (0.010 g, 0.009 mmol). The reaction was sealed and heated to 120 ° C. for 30 minutes in microwave. _Then, the mixture was concentrated in vacuo. This material was diluted with CH ₂ Cl _2, and silica gel chromatography to give the product (63d) by (hexane _{EtOAc → 20% MeOH / CH 2} Cl 2).

LCMS +: 585.25, 4.17 min (10-90% MeOH, 3/5 grad / run, formic acid).

(5S, 7S) -7- (2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -3-methyl -1-oxa-3-azaspiro [4.5] decan-2-one (971)

(5S, 7S) -7- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidine in MeOH (2 mL) In a solution of -4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (63d) (0.035 g, 0.060 mmol) NaOMe (25% w / v 2 mL 9.255 mmol) was added. The mixture was stirred for 30 min, then concentrated in vacuo and purified by reverse phase HPLC (water / HCl: MeOH). Pure fractions were combined and concentrated in vacuo to give product 971 as HCl salt.

Scheme 64

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4- Formation of general] amino] cyclohexanone (64a)

In a microwave tube, 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 in DME (22.2 mL) -Yl) pyrrolo [2,3-b] pyridine (2.13 g, 4.93 mmol) and (3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanone And Na ₂ CO ₃ aqueous solution (5.13 mL of 2M solution, 10.26 mmol) was added. The mixture was deoxygenated with nitrogen for 20 minutes. Tetrakis triphenylphosphane palladium (0.47 g, 0.41 mmol) was added to the reaction mixture. The reaction was sealed and heated to 120 ° C. for 30 minutes. The reaction was diluted with ethyl acetate (40 mL) and filtered through celite. The filtrate was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification via silica gel chromatography using a 10-80% EtOAc / hexanes gradient gave (3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3- b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] cyclohexanone (64a) was obtained.

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4- Formation of Japanese] amino] -1-trimethylsilyloxy-cyclohexanecarbonitrile (64b)

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5 in CH ₂ Cl ₂ (20 mL). In solution of -fluoro-pyrimidin-4-yl] amino] cyclohexanone (64a) (0.58 g, 1.13 mmol) diiodozin (0.36 g, 1.13 mmol) and trimethylsilylformonitrile (0.30 Ml, 2.26 mmol) was added. The reaction was refluxed overnight. The mixture was purified by silica gel chromatography to give (3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl]- 600 mg of 5-fluoro-pyrimidin-4-yl] amino] -1-trimethyl-silyloxy-cyclohexanecarbonitrile (64b) was obtained.

(1S, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino]- Formation of 1-hydroxycyclohexanecarboxylic acid (64c)

(3S) -3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4- Il] amino] -1-trimethylsilyloxy-cyclohexanecarbonitrile (64b) (0.57 g, 0.93 mmol) was heated to 80 ° C. overnight in HCl (20 mL of 12M solution, 240.0 mmol) in a closed tube. The solvent was evaporated and the crude product was purified by preparative HPLC to give (1S, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5 200 mg of -fluoro-pyrimidin-4-yl] amino] -1-hydroxycyclohexanecarboxylic acid (64c) was provided.

(1S, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino]- Formation of N-ethyl-1-hydroxycyclohexanecarboxamide 779

(1S, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino]- 1-hydroxy-cyclohexanecarboxylic acid (64c) (0.040 g, 0.090 mmol) was dissolved in DMF (3 mL), then ⁱ Pr ₂ NEt (0.047 mL, 0.271 mmol) and ethanamine (0.135 mL of 2M solution, 0.271 mmol) was added followed by HATU (0.080 g, 0.210 mmol). The reaction was stirred again at rt for 2 h. The solution was evaporated and the product was purified by preparative HPLC to give (1S, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5- 10 mg of fluoro-pyrimidin-4-yl] amino] -N-ethyl-1-hydroxy-cyclohexanecarboxamide (779) was obtained.

Scheme 65

Formation of 3-Amino-2-hydroxy-cyclohexanecarboxylic acid (65a)

2-hydroxy-3-nitro-benzoic acid (5.0 g, 27.3 mmol) was mixed with HCl (0.5 M 125 mL, 62.5 mmol) and dioxoplatinum (1.0 g, 4.4 mmol) in a hydrogenation bottle. The mixture was placed on a Parr shaker (50 psi H ₂ ) for 24 hours. The catalyst was filtered off and washed with hot H ₂ O. The filtrate was evaporated to give 3-amino-2-hydroxy-cyclohexanecarboxylic acid as a mixture of stereoisomers used in the next step without further purification.

3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] Formation of 2-hydroxycyclohexanecarboxylic acid (65b)

5-Chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) -pyrrolo [2,3-b in DMF (23.2 mL) ] A solution of pyridine (65a) (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19 g, 0.97 mmol) and ⁱ Pr ₂ NEt (0.45 mL, 2.58 mmol) in a microwave Heated to 130 ° C. for 10 minutes. The solvent of the reaction mixture is removed under reduced pressure and the residue is purified by preparative HPLC to give 3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine- 240 mg of 3-yl] -5-fluoro-pyrimidin-4-yl] amino] -2-hydroxy-cyclohexanecarboxylic acid (65b) were obtained as a mixture of stereoisomers.

3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] Formation of -N-ethyl-2-hydroxy-cyclohexanecarboxamide (65c)

3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] 2-Hydroxy-cyclohexanecarboxylic acid (65b) (0.100 g, 0.179 mmol) was dissolved in DMF (2 mL) and ⁱ Pr ₂ NEt (0.124 mL, 0.714 mmol) and ethanamine hydrochloride (0.029 g) at room temperature. 0.357 mmol) was added. This solution was then added HATU (0.081 g, 0.214 mmol) at room temperature. After 30 minutes, EtOAc was added and the mixture was washed with 1N HCl, saturated aqueous NH ₄ Cl and brine. The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude product was used in the next step without further purification.

3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] -N-ethyl-2- Formation of Hydroxy-cyclohexanecarboxamide 815

3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] -N-ethyl-2-hydroxy-cyclohexanecarboxamide (65c) was treated with NaOMe in MeOH. The product was purified by preparative HPLC to give 3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino ] -N-ethyl-2-hydroxy-cyclohexanecarboxamide was provided as a mixture of stereoisomers.

LCMS: 433.35 (M + 1).

Scheme 66

Formation of Methyl-1-methylcyclohex-2-ene-1-carboxylate (66a)

NBuLi (12.65 mL, 27.82 mmol) was added dropwise to a cooled (0 ° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon. After 15 minutes, the solution was cooled to -78 ° C and anhydrous HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred at −78 ° C. for 30 minutes, after which methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was added. After further stirring for 10 minutes, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then warmed to -5 ° C over 2 hours. To the orange mixture was poured saturated aqueous NH ₄ Cl solution. After diluting with hexane and washing with brine, the organic layer is dried over Na ₂ SO ₄ and carefully evaporated to use methyl 1-methylcyclohex-2-ene-1-carboxylate (66a) without further purification. ) 3.3g.

Formation of racemic cis-methyl 5-methyl-7-oxabicyclo [4.1.0] heptan-5-carboxylate (66b)

Methyl 1-methylcyclohex-2-ene-1-carboxylate (66a) (3.30 g, 21.40 mmol) was added 3-chloroperoxybenzoic acid (7.39 g, in CH ₂ Cl ₂ (75 mL) at room temperature for 2 hours. 42.80 mmol). The solution was clear but a white precipitate was observed after 1 hour. The white solid obtained was filtered, washed with hexanes, the filtrate was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ solution and then brine. The organic phase was then dried over Na ₂ SO ₄ , concentrated in vacuo and the crude residue was purified by silica gel chromatography (hexane / ethyl acetate 100/0 → 10/1 gradient) to give two products. The less polar spot is a colorless oil, which is designated cis-methyl 5-methyl-7-oxabicyclo [4.1.0] heptan-5-carboxylate (1.2 g) by 1 H NMR, the second fraction being It is a white solid, which is trans-methyl-5-methyl-7-oxabicyclo [4.1.0] heptan-5-carboxylate (2.2 g).

Racemic cis-isomer (66b):

Formation of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate (66c)

Racemic cis-methyl-5-methyl-7-oxabicyclo [4.1.0] heptan-5-carboxylate (66b) (2.2 g, 12.93 mmol) was added to MeOH (90 mL) and H ₂ O ( 10 ml) was added to the flask. NH ₄ Cl (1.38 g, 0.90 mL, 25.86 mmol) and NaN ₃ (2.52 g, 38.79 mmol) were then added to the reaction mixture. The mixture was heated at reflux for 16 h. The solvent was evaporated under reduced pressure, the oil was taken up in H ₂ O and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na ₂ S0 ₄ . The crude product was purified by silica gel chromatography to give 900 mg of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate.

Formation of racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate (66d)

A solution of racemic methyl-3-azido-2-hydroxy-1-methyl-cyclohexane-carboxylate (66c) (0.90 g, 4.22 mmol) in a mixture of MeOH (50 mL) and AcOH (10 mL) was added. Stirred overnight at room temperature in the presence of palladium (0.50 g, 0.47 mmol) in a hydrogen atmosphere (balloon). The mixture was filtered through a celite bed and washed with MeOH. The combined filtrates were evaporated to give methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as an oil. Et ₂ O was added and the resulting acetate was stirred for 0.5 hour, then filtered to give 1.0 g of racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate acetate as a white solid. Obtained.

Formation of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66e)

2,4-dichloro-5-fluoro-pyrimidine (0.43 g, 2.58 mmol) and racemic methyl-3-amino-2-hydroxy-1- in THF (10 mL) and MeOH (8 mL) at room temperature To a solution of methyl-cyclohexanecarboxylate acetate (66d) (0.58 g, 2.35 mmol) ⁱ Pr ₂ NEt (1.23 mL, 7.04 mmol) was added. After the reaction was stirred at rt overnight, the solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography (hexane / EtOAc 100/0 → 0/100, Rf = 0.7 in hexane / EtOAc 2/1). To 650 mg of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66e) as a white solid. Provided.

LCMS: 318.16 (M + l).

Racemic methyl-3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4- Formation of Japanese] amino] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66f)

Racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66e) in THF (20 mL) ( 0.65 g, 2.05 mmol) and 5-chloro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) To a solution of pyrrolo [2,3-b] pyridine (1.32 g, 3.05 mmol) was added aqueous Na ₂ CO ₃ (3.52 mL of 2M solution, 7.04 mmol). The solution was degassed with N ₂ for 20 minutes. Tetrakis triphenylphosphane palladium (0) (0.14 g, 0.12 mmol) was added and the mixture was refluxed overnight. LCMS showed good conversion but some starting material remained. Further degassed 2N Na ₂ CO ₃ was added followed by another portion of tetrakis triphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction was again refluxed for 4 hours. The mixture was cooled to rt and extracted with EtOAc. The organic phase was washed with brine and dried over Na ₂ S0 ₄ . After evaporating the solvent, the crude mixture was purified by silica gel chromatography (hexane / EtOAc 100/0 → 0/100) to give racemic methyl-3-[[2- [5-chloro-1- (p-tol). Rylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidin-4-yl] amino] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66f) 1.0 g was given.

LCMS: 588.26 (M + l).

(1S, 2S, 3S) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid (928)

Racemic methyl-3-[[2- [5-chloro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridin-3-yl] -5-fluoro-pyrimidine-4- Ill] amino] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66f) (0.100 g, 0.170 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) and aqueous LiOH (1M solution 0.24 ML, 0.24 mmol) and the reaction was heated at reflux overnight. The reaction was cooled to room temperature and the material obtained was purified directly by preparative HPLC to give racemic 3-[[2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5 20 mg of -fluoro-pyrimidin-4-yl] amino] -2-hydroxy-1-methylcyclohexanecarboxylic acid was obtained. Enantiomers of racemic material were separated by chiral SFC purification to give (1R, 2R, 3R) -3-[[2- (5-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid 6 mg and (1S, 2S, 3S) -3-[[2- (5-chloro- 6 mg of 1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl] amino] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid was obtained. .

LCMS: 420.36 (M + l).

Scheme 67

(a) Pd / C (wet, degussa), hydrogen, EtOH (b) 2,4-dichloro-5-fluoropyrimidine, ⁱ Pr ₂ NEt, THF, reflux (c) LiOH, THF / water, 50 (D) DPPA, Et ₃ N, THF, 85 ° C. (e) 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, XPhos, Pd ₂ (dba) ₃ , K ₃ PO ₄ , 2-methylTHF, water, 125 ° C. (f)

Formation of (1R, 3S) -ethyl 3-aminocyclohexanecarboxylate (67b)

Pd / C (wet, degussa) in a solution of (1R, 3S) -ethyl 3- (benzyloxycarbonylamino) cyclohexane-carboxylate (18b) (14.0 g, 45.9 mmol) in ethanol (3 mL) ( 2.4 g, 2.3 mmol) was added. After the mixture was evacuated, it was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was filtered through a pad of celite and the filtrate obtained was concentrated in vacuo to give an oil which was used without further purification.

Formation of (1R, 3S) -ethyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylate (67c)

(1R, 3S) -Ethyl 3-aminocyclohexanecarboxylate (67b) (5.1 g, 24.1 mmol) and 2,4-dichloro-5, -fluoropyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) To the solution of was added diisopropylethylamine (9.6 mL, 55.4 mmol). The mixture was heated at reflux overnight. The reaction was cooled to rt and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc / hexane gradient) to give (1R, 3S) -ethyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane- 6.7 g of carboxylate was provided as a white solid.

LCMS RT = 3.1 (M + H) 302.2.

Formation of (1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (67d)

To a solution of (1R, 3S) -ethyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylate (67c) (20.0 g, 66.3 mmol) in THF (150 mL) LiOH hydrate solution (8.3 g, 198.8 mmol) in 100 mL water was added. The reaction mixture was stirred at 50 ° C. overnight. To the reaction mixture was added HCl (16.6 mL of 12M solution, 198.8 mmol) and EtOAc. The organic phase was washed with brine, dried over MgSO ₄ and the solvent removed under reduced pressure to give 17.5 g of product used without further purification.

Formation of N-((1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexyl) -pyrrolidine-1-carboxamide (67e)

(1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylic acid (67d) (8.2 g, 30.0 mmol) in THF (200 mL), (Azido ( A solution of phenoxy) phosphoryl) oxybenzene (9.7 mL, 45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) was degassed under nitrogen for 15 minutes. The reaction mixture was heated to 85 ° C. for 30 minutes until LC / MS showed complete consumption of carboxylic acid (67d). Pyrrolidine (7.5 mL, 90.0 mmol) was added to the reaction mixture, and the reaction was heated to 85 ° C. for an additional 15 minutes. The mixture was diluted with brine and extracted with EtOAc. The organic phase was separated and dried over MgSO ₄ . The product (6.25 g) was isolated by filtration after partial removal of the solvent in vacuo.

N-((1R, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4 Formation of -ylamino) cyclohexyl) pyrrolidine-1-carboxamide (67f)

N-((1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexyl) -pyrrolidine in 2-methyl THF (180 mL) and water (20 mL) -1-carboxamide (67e) (6.8 g, 20.0 mmol), 5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3, A solution of 2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (44a) (12.5 g, 30.0 mmol) and K ₃ PO ₄ (17.0 g, 80.0 mmol) under nitrogen for 30 minutes It was degassed. To the mixture was added dicyclohexyl- [2- (2,4,6-triisopropylphenyl) phenyl] phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd ₂ (dba) ₃ (0.5 g, 0.5 mmol). Added. The reaction mixture was heated to 125 ° C. for 2.5 hours in a pressure bottle. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The residue obtained was purified by silica gel chromatography (8% MeOH / CH ₂ Cl ₂ ) to give 11.5 g of the desired product.

N-((1R, 3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -pyrimidin-4-ylamino Formation of Cyclohexyl) Pyrrolidine-1-Carboxamide (895)

N-((1R, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3- in THF (150 mL) To a solution of 1) pyrimidin-4-ylamino) cyclohexyl) pyrrolidine-1-carboxamide (67f) (11.5 g, 19.3 mmol) was added sodium methoxide (4.173 g, 19.31 mmol). After the reaction mixture was stirred for 2 minutes, the mixture was poured into saturated aqueous NaHCO ₃ solution. The organic phase was washed with brine, dried over MgSO ₄ and the solvent removed under reduced pressure. The obtained residue was purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 6.5 g of the desired product. The product was dissolved in MeOH (100 mL) and converted to HCl salt by adding 2.4 mL of 12M HCl solution at room temperature. The solution was stirred for 1 hour and the HCl salt was precipitated and filtered to give 7.05 g of HCl salt.

Scheme 68

(a) TsCl, NaH, DMF, 45 ° C. (b) Methyl iodide, K ₂ CO ₃ , DMF (c) Bromine, CHCl ₃ , 0 ° C. to room temperature (d) Bis (pinacol) diborane, palladium (II) Dichloro bis (tricyclohexylphosphane), KOAc, 2-methylTHF, 125 ° C. (e) (R) -N-((1R, 3S) -3-((2-chloro-5-fluoropyrimidine- 4-yl) amino) cyclohexyl) -3-fluoropyrrolidine-1-carboxamide, XPhos, Pd ₂ (dba) ₃ , K ₃ PO ₄ , 2-methylTHF, water, 125 ° C.

Formation of 5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-ol (68a)

Toluenesulfonyl chloride (1.8 g, 9.5 mmol) was added to a solution of 5-fluoro-1H-pyrrolo [2,3-b] pyridin-4-ol (1.2 g, 7.9 mmol) in 80 mL of DMF at 0 ° C. After addition, NaH (0.8 g, 19.7 mmol, 60% w / w) was added. After 3 hours the reaction was slowly warmed to 45 ° C. and stirred for an additional 3 hours. Then the mixture was concentrated in vacuo. The crude oil was dissolved in 100 mL of EtOAc and washed with water (2 × 50 mL) and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (10% EtOAc / hexanes) to afford 1.5 g of the desired product.

Formation of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo [2,3-b] pyridine (68b)

To a solution of 5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-ol (68a) (0.70 g, 2.29 mmol) in DMF (25 mL), methyl iodide (0.14 mL, 2.29 mmol) and K ₂ CO ₃ (0.32 g, 2.29 mmol) were added. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with deionized water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 720 mg of the desired product to be used in the next step without further purification.

Formation of 5-fluoro-4-methoxy-3-bromo-1-tosyl-1H-pyrrolo [2,3-b] pyridine (68c)

To a cooled (0 ° C.) solution of 5-fluoro-4-methoxy-1-tosyl-1H-pyrrolo [2,3-b] pyridine (68b) (0.79 g, 2.45 mmol) in chloroform (50 mL). Bromine (0.13 mL, 2.45 mmol) was added. The reaction mixture was stirred at 0 ° C. for 3 hours and then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chloride and dried over sodium sulfate. The obtained solid was purified via silica gel chromatography (15-30% EtOAc / hexanes) to give 170 mg of the desired product.

5-fluoro-4-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2 , 3-b] formation of pyridine (68d)

5-fluoro-4-methoxy-3-bromo-1-tosyl-1H-pyrrolo [2,3-b] pyridine (68c) in 2-Me-THF (9 mL) in a microwave vial ( After adding bis (pinacol) diborane (0.16g, 0.64mmol) to a solution of 0.17g, 0.43mmol), potassium acetate (0.23g, 1.06mmol) and palladium (II) dichlorobis (tricyclohexylphosphane) ) (0.02 g, 0.02 mmol) was added. The reaction vial was sealed and microwave irradiated at 125 ° C. for 90 minutes. The mixture was filtered and purified via silica gel chromatography (10-30% EtOAc / hexanes) to give 100 mg of the desired product.

(R) -3-fluoro-N-((1R, 3S) -3-((5-fluoro-2- (5-fluoro-4-methoxy-1H-pyrrolo [2,3-b ] Pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide (1104)

5-Fluoro-4-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in 2-Me-THF (2 mL)- To a solution of 1-tosyl-1H-pyrrolo [2,3-b] pyridine (68d) (0.100 g, 0.220 mmol), (R) -N-((1R, 3S) -3-((2-chloro- 5-fluoropyrimidin-4-yl) amino) cyclohexyl) -3-fluoropyrrolidine-1-carboxamide (0.060 g, 0.170 mmol) was added. Potassium phosphate (0.130 g, 0.600 mmol) and deionized water (0.5 mL) were then added and the solution was degassed for 10 minutes under nitrogen flow. 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos) (0.006 g, 0.012 mmol) and tris (dibenzylideneacetone) -dipalladium (0) (0.023 Mg, 0.026 mmol) was added and the solution was degassed again under nitrogen flow for 5 minutes. The vial was sealed and heated to 80 ° C. for 3 hours. The solution was cooled to ambient temperature, filtered and concentrated in vacuo. The crude oil was dissolved again in dry THF (5 mL) and 2N LiOH solution (2 mL) was added. The reaction mixture was heated to 80 ° C. for 2 hours. The solution was cooled to ambient temperature and concentrated in vacuo. Purification by preparative HPLC gave 6 mg of the desired product.

Scheme 69

(a) NaCN, LiClO ₄ , CH ₃ CN (b) 5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl) pyrrolo [2,3-b] pyridine, Na ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dimethoxyethane, 120 ° C. (c) sodium methoxide, MeOH

Formation of 2-((1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) -ethanenitrile (69a)

2-chloro-5-fluoro-N-[(3S) -1-oxaspiro [2.5] octan-7-yl] pyrimidin-4-amine (49c) (0.50 g, 1.94 mmol) in CH ₃ CN, A suspension of NaCN (0.11 g, 2.33 mmol) and lithium perchlorate (0.25 g, 2.33 mmol) was heated to 100 ° C. for 3 hours in a pressure tube. The mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. The residue obtained was purified by silica gel chromatography (EtOAc / hexanes) to afford the desired product.

2-((1S, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4 Formation of -ylamino) -1-hydroxycyclohexyl) ethanenitrile (69b)

5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- in dimethoxyethane (15 mL) Yl) pyrrolo [2,3-b] pyridine (44a) (0.23 g, 0.55 mmol), 2-((1S, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino A solution of) -1-hydroxycyclohexyl) -ethanenitrile (69a) (0.14 g, 0.50 mmol) and Na ₂ CO ₃ (0.75 mL of 2M solution, 1.50 mmol) was degassed with nitrogen for 30 minutes. Palladium in the reaction mixture; Triphenylphosphane (0.03 g, 0.03 mmol) was added and the solution was continued to degas for 15 minutes. The reaction mixture was heated to 120 ° C. for 45 minutes in a pressure tube. The reaction mixture was filtered through celite and the filtrate was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (40% EtOAc / hexanes) to give 150 mg of the desired product.

LCMS RT = 3.55 (M + H) 539.42.

2-((1S, 3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) ethane nitrile (979)

2-((1S, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3- in methanol (10 mL) To the solution of I) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) ethanenitrile (69b) (0.14 g, 0.26 mmol) was added sodium methoxide (0.06 g, 0.26 mmol). After stirring for 2 minutes at room temperature, the reaction mixture was diluted with EtOAc and brine. The separated organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 46 mg of the desired product.

Scheme 70

(a) tert-butyl N- (N-tert-butoxycarbonyl-C-pyrazol-1-yl-carbonimidoyl) carbamate, CH ₂ Cl ₂ (b) 5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine, Na ₂ CO ₃ , Pd (PPh ₃ ) ₄ , dimethoxyethane, 120 ° C. (c) sodium methoxide, THF, MeOH

Tert-butyl (tert-butoxycarbonylamino) ((1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylamino) methylenecarbamate (70b) Formation of

(1S, 3R) -N1- (2-Chloro-5-fluoro-pyrimidin-4-yl) cyclohexane-1,3-diamine (70a) (0.122 g, 0.500) in CH ₂ Cl ₂ (10 mL) To a solution of mmol) was added tert-butyl N- (N-tert-butoxycarbonyl-C-pyrazol-1-yl-carbonimidoyl) carbamate (0.155 g, 0.500 mmol). The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was concentrated in vacuo and used without further purification.

LCMS RT = 3.97 (M + H) 487.12.

Tert-butyl N- [N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) -pyrrolo [2,3- b] pyridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] carbamimidoyl] -carbamate (70c) formation

(Z) -tert-butyl (tert-butoxycarbonylamino) ((1R, 3S) -3- (2-chloro-5-fluoropyrimidin-4-yl) in dimethoxyethane (15 mL) Amino) cyclohexylamino) methylenecarbamate (70b) (0.200 g, 0.411 mmol), 5-fluoro-1- (p-tolylsulfonyl) -3- (4,4,5,5-tetramethyl-1 A solution of, 3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (44a) (0.205 g, 0.493 mmol) and Na ₂ CO ₃ (0.616 mL, 1.232 mmol) Was degassed for 30 minutes. Palladium triphenylphosphane (0.023 g, 0.021 mmol) was added to this mixture, and the reaction mixture was heated to 120 ° C. for 45 minutes in a pressure tube. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue obtained was purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ) to give a mixture mainly containing the desired product which was used without further purification.

LCMS RT = 2.30 (M + H) 641.02.

1-((1R, 3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) Formation of cyclohexyl) guanidine (1143)

Tert-butyl N- [N-[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo in THF (20 mL) In a solution of [2,3-b] pyridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] carbamidoyl] carbamate (70c) (0.100 g, 0.156 mmol), sodium methoxide ( 0.033 g, 0.156 mmol) was added. After 1 minute, the reaction mixture was diluted with EtOAc and saturated aqueous NaHCO ₃ solution. The organic phase was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. The obtained residue was purified by silica gel chromatography to give 95 mg of the desired product. To 10 mL of MeOH solution of the product was added hydrochloride / IPA (0.031 mL of 5M solution, 0.156 mmol). After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure to give the product as a hydrochloride salt.

Scheme 71

(a) DBU, methyl 2-chlorooxazole-4-carboxylate, DMF, 75 ° C. (b) LiOH, THF

Methyl 2-((1R, 3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine- Formation of 4-ylamino) cyclohexylamino) oxazole-4-carboxylate (71a)

(1S, 3R) -N1- [5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine-3- in DMF (1.5 mL) Methyl 2-chlorooxazole-4-carboxylate (0.031 g, 0.195 mmol) was added to a solution of il] pyrimidin-4-yl] cyclohexane-1,3-diamine (44e) (0.089 g, 0.178 mmol). Then DBU (0.029 mL, 0.195 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction was warmed to 75 ° C. and stirred for 3 hours. Further 16 mg of chlorooxazole ester were added and the reaction was heated to 75 ° C. overnight. The mixture was diluted with water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-20% MeOH / CH ₂ Cl ₂ ) to give 28 mg of the desired product.

LCMS RT = 3.73 (M + l) 624.12.

2-((1R, 3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) Formation of Cyclohexylamino) oxazole-4-carboxylic Acid (1144)

Methyl 2-[[(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) -pyrrolo [2,3 in THF (1 mL)) -b] pyridine-3-yl] pyrimidin-4-yl] amino] cyclohexyl] -amino] oxazole-4-carboxylate (71a) (0.028 g, 0.045 mmol) in a solution of LiOH (1 M solution) , 1.000 mmol) was added and the reaction mixture was warmed to 130 ° C. via microwave irradiation. After heating and stirring for 20 minutes, the mixture was cooled to room temperature. All volatiles were removed under nitrogen stream and heating. The crude residue was suspended in MeOH and trifluoroacetic acid drops were added to quantify the molecules (solution developed). The mixture was filtered and purified by reverse phase HPLC (5-95% CH ₃ CN / H ₂ O) to give 5 mg of the desired product as a TFA salt.

Scheme 72

(a) NaHCO ₃ , Br ₂ , H ₂ O (b) NaOH (c) TMSCl, MeOH (d) Sodium methoxide, MeOH, 150 ° C. (e) Sodium borohydride, MeOH (f) Ethyl 2- (tertiary -Butoxycarbonylamino) -2-oxo-acetate, DEAD, PPh ₃ , 85 ° C. (g) NaOH, MeOH (h) trifluoroacetic acid, CH ₂ Cl ₂ , 1N HCl / ether (i) 5-fluor Rho-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine, ⁱ Pr ₂ NEt, THF (j ) Lithium hydroxide, THF (k) DPPA, Et ₃ N, pyrrolidine

Formation of 6-bromohexahydro-2H-3,5-methanocyclopenta [b] furan-2-one (72a)

To a solution of bicyclo [2.2.1] hept-5-ene-3-carboxylic acid (25.0 mL, 204.3 mmol) in NaHCO ₃ (51.5 g, 612.9 mmol) in water, bromine (32.7 g, 204.3 mmol) was added at 0 ° C. Added dropwise. The solution is stirred for 1 hour, extracted with ether, the organic phase is washed successively with 1N Na ₂ S ₂ SO ₃ solution and brine, the organic phase is dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. 30 g of crude product were used without further purification.

Formation of 6-oxonorbornane-2-carboxylic acid (72b)

6-Bromohexahydro-2H-3,5-methanocyclopenta [b] furan-2-one (72a) (28.0 g, 129.0 mmol) was dissolved in NaOH in H ₂ O (350 mL) for 2 hours at room temperature. (258.0 mL, 516.0 mmol) of 2M solution. The reaction mixture was acidified with concentrated HCl and extracted with Et ₂ O. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified by silica gel chromatography (0-20% MeOH / CH ₂ Cl ₂ gradient) to give 16 g of 6-oxonorbornane-2-carboxylic acid.

Formation of Endo Methyl 6-oxonorbornane-2-carboxylate (72c)

A solution of 6-oxonorbornane-2-carboxylic acid (72b) (16.0 g, 103.8 mmol) in methanol (350.0 mL) was treated with TMSCl (42.04 g, 49.11 mL, 387.0 mmol). The reaction mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (10% EtOAc / hexanes) to give 12 g of endo methyl 6-oxonorbornane-2-carboxylate.

Formation of Exo Methyl 6-Oxonorbornane-2-carboxylate (72d)

Endo methyl 6-oxonorbornane-2-carboxylate (72c) (3.5 g, 20.8 mmol) was heated to 150 ° C. in sodium methoxylate (2.1 mL of 2M solution in methanol, 4.2 mmol) for 17 h in a closed tube. It was. The solvent was evaporated and the crude product was purified by silica gel chromatography (0-16% EtOAc / hexane gradient), starting starting methyl methyl 6-oxonorbornane-2-carboxylate 3.3 as first fraction (PMA staining). g was obtained and 4.0 g of the desired exo product was obtained as the second spot. The recovered starting material was again subjected to the same conditions to yield another 1.0 g of the desired exo-product.

Formation of Methyl 6-hydroxynorbornane-2-carboxylate (72e)

A solution of exo methyl 6-oxonorbornane-2-carboxylate (72d) (4.7 g, 27.9 mmol) in MeOH (50 mL) was partitioned into five times sodium borohydride (1.6 g, 41.9 mmol) at 0 ° C. Added. After 2 hours TLC showed complete conversion. The reaction was quenched by addition of saturated aqueous NH ₄ Cl solution. After MeOH was evaporated under reduced pressure, the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue obtained was purified by silica gel chromatography (0-100% EtOAc / hexanes, Rf = 0.5 in 50% EtOAc / hexanes) to afford 3.96 g of the desired product.

Formation of Methyl 6- (N- (tert-butoxycarbonyl) -2-ethoxy-2-oxoacetamido) bicycle [2.2.1] heptane-2-carboxylate (72f)

To a cooled (0 ° C.) solution of methyl 6-hydroxynorbornane-2-carboxylate (72e) (3.2 g, 18.8 mmol) in THF (150 mL) ethyl 2- (tert-butoxycarbonylamino) 2-oxo-acetate (4.9 g, 22.6 mmol) and triphenylphosphine (5.9 g, 22.6 mmol) were added followed by the dropwise addition of diisopropyl azodicarboxylate (4.5 g, 22.6 mmol). The reaction was then heated to 85 ° C. and held at this temperature for 2 days. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (0-100% EtOAc / hexane gradient) to give methyl 6- (N- (tert-butoxycarbonyl) -2-ethoxy-2 6 g of oxoacetamido) bicyclo [2.2.1] heptan-2-carboxylate was provided.

Formation of 6- (tert-butoxycarbonylamino) norbornane-2-carboxylic acid (72 g)

Methyl 6- [tert-butoxycarbonyl- (2-ethoxy-2-oxo-acetyl) amino] norbornane-2-carboxylate (72f) (0.80 g, 2.17 mmol) in methanol (20 mL) To a solution of was added NaOH (4.33 mL of 2N solution, 8.66 mmol) at room temperature. The reaction mixture was stirred overnight. The mixture was diluted with 0.5N HCl in ice and extracted twice with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to yield 600 mg of the desired product to be used without further purification.

Formation of 6-aminobicyclo [2.2.1] heptane-2-carboxylic acid (72h)

A solution of 6- (tert-butoxycarbonylamino) norbornane-2-carboxylic acid (72 g) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the product obtained was dissolved in 2 mL of THF and added to the stirring 1N HCl / Et ₂ O solution. After the mixture was stirred for 0.5 h, the obtained precipitate was filtered and washed with anhydrous Et ₂ O to give 6-aminobicyclo [2.2.1] heptane-2-carboxylic acid.

6- (5-Fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-ylamino) bicyclo [2.2.1] heptane- Formation of 2-carboxylic Acid (72j)

5-Fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b in THF (3 mL) ] Diisopropylethylamine (0.291 mL, 1.670 mmol) in a solution of pyridine (0.187 g, 0.417 mmol) and 6-aminobicyclo- [2.2.1] heptane-2-carboxylic acid (72 h) (0.080 g, 0.417 mmol) ) Was added. The reaction mixture was heated to 80 ° C. overnight. Aqueous LiOH (3 mL of 2M solution, 6.000 mmol) was added and the mixture was heated again for 7 h. The mixture was diluted with MeOH, neutralized with trifluoroacetic acid, filtered and the filtrate obtained was purified by preparative HPLC chromatography to give 50 mg of the desired product.

N- [6-[[5-fluoro-2- (5-fluoro-1 H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] norbornane- Formation of 2-yl] pyrrolidine-1-carboxamide (1045)

6-[[5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl] amino] nor in THF (0.375 mL) Triethylamine (0.032 mL, 0.234 mmol) and (Azido (phenoxy) phosphoryl) oxybenzene (0.018 mL, 0.085 mmol) were added to a solution of bornan-2-carboxylic acid (72j) (0.030 g, 0.078 mmol). Added. The reaction mixture was heated to 95 ° C. for 2.5 h, cooled to 5 ° C. and treated with pyrrolidine (0.010 mL, 0.117 mmol). The reaction was stirred at rt for 3 days. The reaction mixture was injected directly into the preparative HPLC system for purification to provide the product as a racemic mixture. Separation using SFC chiral tablets afforded single enantiomers to obtain 5.7 mg of the desired product as well as 1.4 mg of the enantiomer.

Scheme 73

(a) ⁱ Pr ₂ NEt, THF, reflux (b) 1N LiOH, THF / H ₂ O, 130 ° C., microwave

(1R, 2R, 3S) -3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4 -Yl) amino) cycloheptan-1,2-diol (73b)

Aminodiol (73a) was synthesized according to the method of JOC 2009, 74, 6735. Aminodiol (0.040 mg), diisopropylethylamine (0.054 mL, 0.310 mmol) in THF and 5-fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1 -(p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (0.139 g, 0.310 mmol) was refluxed overnight. The solution was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc / CH ₂ Cl ₂ ) to give 43 mg of the desired product as a white solid.

(1R, 2R, 3S) -3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino Formation of Cycloheptane-1,2-diol (984)

LiOH (0.5 mL of 1N solution, 0.5 mmol) was added to (1R, 2R, 3S) -3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo) in THF (3 mL). [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) cycloheptan-1,2-diol (73a). The reaction mixture was heated to 130 ° C. for 40 minutes in a microwave. HCl (0.5 mL of 1.25N solution in MeOH) and MeOH were added to the mixture. The solution was purified by preparative HPLC (MeCN / H ₂ O 10-70%) to afford the desired product as a TFA salt. Neutralization and acidification again with hydrogen chloride (IN in MeOH) gave the desired product (28 mg) as a white solid (HCl salt).

Scheme 74

(a) CuI, 2- (2-methylpropanoyl) cyclohexanone, DMF (b) H ₂ , Pd / C, MeOH (c) 5-fluoro-3- (5-fluoro-4-methyl Sulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (d) 1N LiOH, THF / H ₂ O, 130 ° C. microwave

Formation of benzyl ((1S, 3R) -3- (pyrazin-2-ylamino) cyclohexyl) carbamate (74a)

CuI (0.006 g, 0.030 mmol), benzyl N-[(1S, 3R) -3-aminocyclo-hexyl] carbamate (18e) (0.075 g, 0.302 mmol) and cesium carbonate (0.197 g, 0.604 mmol) in DMF The suspension of was evacuated and backfilled with nitrogen several times. Then 2-iodopyrazine (0.036 mL, 0.362 mmol) and 2- (2-methylpropanoyl) cyclohexanone (0.020 mL, 0.121 mmol) were added and the reaction stirred at room temperature overnight. The reaction was diluted with ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH / CH ₂ Cl ₂ ) to afford 40 mg of the desired product as a yellow solid.

Formation of (1R, 3S) -N1- (pyrazin-2-yl) cyclohexane-1,3-diamine (74b)

To a solution of benzyl N-[(1S, 3R) -3- (pyrazin-2-ylamino) cyclohexyl] carbamate (74a) (0.040 g, 0.123 mmol) in methanol (10 mL) was added 10% Pd / C ( 0.043 g, 0.040 mmol) was added and the resulting suspension was stirred for 3 h under hydrogen atmosphere until LCMS indicated complete reaction. The solution was filtered through a celite bed and concentrated in vacuo to yield a yellow solid that was used without further purification.

(1S, 3R) -N1- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) Formation of -N3- (pyrazin-2-yl) cyclohexane-1,3-diamine (74c)

(1R, 3S) -N1-pyrazin-2-ylcyclohexane-1,3-diamine (74b), diisopropylethylamine (0.30 mmol) and 5-chloro-3- (5- in THF (3 mL) A solution of fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-tolylsulfonyl) -pyrrolo [2,3-b] pyridine (0.06 g, 0.13 mmol) was refluxed overnight. . The mixture was then concentrated in vacuo and the residue obtained was purified by silica gel chromatography (0-20% MeOH / CH ₂ Cl ₂ gradient) to afford 39 mg of the desired product.

(1S, 3R) -N1- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) -N3- ( Formation of Pyrazin-2-yl) cyclohexane-1,3-diamine (985)

LiOH (0.3 mL of 1N solution, 0.3 mmol) was dissolved in THF (3 mL) in (1S, 3R) -N1- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2, 3-b] pyridin-3-yl) pyrimidin-4-yl) -N3- (pyrazin-2-yl) cyclohexane-1,3-diamine (74c) (35 mg) and add the reaction Heated at 130 ° C. in a microwave for 40 minutes. HCl solution (0.5 mL of 1.25N in MeOH) was added and the resulting solution was purified by Gilson HPLC (MeCN / H ₂ O 10-70%, within 8 minutes) to give pure TFA salt product. Neutralization and acidification again with hydrogen chloride (1.25 N in MeOH) gave 23 mg of HCl salt of the desired product as a pale yellow solid.

Scheme 75

(a) NaBH ₄ , MeOH (b) 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H -Pyrrolo [2,3-b] pyridine, 2-Me-THF, water, K ₃ PO ₄ , Pd (PPh ₃ ) ₄ , XPhos, tris (dibenzylideneacetone) dipalladium, reflux (c) bis ( 2,5-dioxopyrrolidin-1-yl) carbonate, ⁱ Pr ₂ NEt, CH ₃ CN (d) (3R) -3-fluoropyrrolidine, ⁱ Pr ₂ NEt, CH ₃ CN (e) 2N LiOH, THF

Formation of (1R, 3S) -3-((2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexanol (75a)

(3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanone (18e) (1.05 g, 4.31) in MeOH (20 mL) and dichloromethane (10 mL). mmol) were mixed and cooled to -78 ° C using an external dry ice / acetone bath and monitored by an internal thermometer. After 30 minutes, NaBH ₄ (0.16 g, 4.31 mmol) was added in one portion and stirring continued (slightly exotherm). Then cooled back to -78 ° C. The reaction was monitored by HPLC for consumption of starting material while warming to room temperature overnight. The reaction was diluted with brine and EtOAc. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography to yield 1.0 g of a colorless foamy solid.

LCMS method m201: 10-90 CH ₃ CN / H ₂ O, formic acid modifier, 5 minutes, (C18); RT = 2.08 min, MH <+> 246.21.

(1R, 3S) -3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl Formation of () amino) cyclohexanol (75b)

K ₃ PO ₄ (2.59 g, 12.21 mmol) in water (6 mL) and 2-Me-THF (20 mL) was purged with nitrogen flow for 30 minutes. (1R, 3S) -3-[(2-chloro-5-fluoro-pyrimidin-4-yl) amino] cyclohexanol (75a) (1.00 g, 4.07 mmol) and 5-fluoro-3- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (44a) (2.03 g, 4.88 mmol) was purged with nitrogen again for 15 minutes. The reaction was then heated to 70 ° C. and then charged with tris (dibenzylideneacetone) dipalladium (0.07 g, 0.08 mmol) and X-Phos (0.14 g, 0.28 mmol) under nitrogen. (Note the color changes from purple to yellow green). The reaction was heated at reflux for 1 h 20 min. The reaction was cooled slowly to room temperature overnight. The mixture was treated with 100 mL brine and 100 mL ethyl acetate and the two layers were separated. The aqueous phase was extracted again with EtOAc (50 mL). The organic layers were combined, passed through a plug of fluorosilyl, dried over Na ₂ SO ₄ , decanted and the solvent removed by rotary evaporation to afford the crude product which was then subjected to silica gel chromatography (25-50). % EtOAc / hexanes) to afford the desired product.

2,5-dioxopyrrolidin-1-yl ((1S, 3R) -3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] Pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl) carbonate (75c)

(1R, 3S) -3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -pyrimidine-4- I) amino) cyclohexanol (75b) (0.50 g, 1.00 mmol) and bis (2,5 in CH ₃ CN (4 mL) in a solution of N, N-diisopropylethylamine (1.40 mL, 10.01 mmol) -Dioxopyrrolidin-1-yl) carbonate (1.28 g, 5.01 mmol) was added and stirred overnight at room temperature. The reaction mixture was used as is for subsequent reactions.

Using LCMS method m201: 10-90 CH ₃ CN / H ₂ O, formic acid modifier, 5 min, (C18); RT = 3.73 min, MH &lt; + &gt; = 641.43 (strong).

(R)-(1S, 3R) -3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine Formation of -4-yl) amino) cyclohexyl 3-fluoropyrrolidine-1-carboxylate (75d)

(2,5-dioxopyrrolidin-1-yl) [(1R, 3S) -3-[[5-fluoro-2- [5-fluoro-1- (p-tolylsulfonyl) in acetonitrile (3R) -3-fluoropyrrolidine to pyrrolo [2,3-b] pyridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] carbonate (75c) (0.125 g, 0.195 mmol) (0.445 g, 4.991 mmol) was added and the reaction mixture was stirred at rt for 20 h and the reaction was monitored by HPLC until no starting material remained. The reaction mixture was concentrated in vacuo and the subsequent reaction proceeded without further purification.

(S)-(1S, 3R) -3-((5-Fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -pyrimidine-4- Formation of I) amino) cyclohexyl 3-fluoropyrrolidine-1-carboxylate (1151)

Crude (R)-(1S, 3R) -3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine in THF (2 mL) 5 ml of 2N LiOH (10 mmol) was added to a solution of -3-yl) pyrimidin-4-yl) amino) cyclohexyl 3-fluoropyrrolidine-1-carboxylate (75d) (0.119 g, 0.019 mmol). It was. The reaction mixture was heated to 50 ° C. for 2 hours. The mixture was diluted with aqueous saturated ammonium chloride (2 mL), extracted with EtOAc (2 × 10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by semi-preparative HPLC (10-70% CH ₃ CN / H ₂ O; run 3 times); The homogeneous fractions were combined, the solvent was removed under a nitrogen stream and the residual solvent was removed on a rotary evaporator to give 74 mg of the desired product.

LCMS RT = 2.15 min (M + H) 461.51.

Scheme 76

(a) Rh / Al ₂ O ₃ , H ₂ O _, 100 ° C., 105 atm H ₂ , 19 h (b) 2,4-dichloro-5-fluoropyrimidine, IPA, MeCN, room temperature (c) CDI, ⁱ Pr ₂ NEt, (S) -3-fluoropyrrolidine, THF, RT, 2 days (d) 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3 -b] pyridine, MeTHF, K ₃ PO ₄ , X-Phos, Pd ₂ dba ₃ , H ₂ O, microwave, 120 ° C., 20 min (e) 25% NaOMe / MeOH, RT, 30 min. (f) SFC separation

Formation of 5-methylcyclohexane-1,3-diamine (76a)

3-methyl-5-nitroaniline (10.0 g, 65.7 mmol) was added to water (146 mL) and treated with 6N HCl (22.5 mL, 135.0 mmol) and 5% alumina supported rhodium (1.9 g, 0.9 mmol). . The mixture was charged with 105 atm of hydrogen and heated to 100 ° C. for 19 h. The reaction was cooled, filtered through celite and concentrated to dryness to afford 5-methylcyclohexane-1,3-diamine dihydrochloride (12.9 g, 64.5 mmol) as a racemic mixture. This salt (6.5 g, 32.5 mmol) was dissolved in isopropyl alcohol (100 mL) and acetonitrile (100 mL) and treated with potassium carbonate (25.2 g, 182.0 mmol). The mixture was stirred at rt overnight, filtered through celite and concentrated in vacuo to yield 2.2 g of 5-methylcyclohexane-1,3-diamine as brown racemic oil.

LCMS RT = 0.41 (M + 1) 128.9.

Formation of N ^1- (2-chloro-5-fluoropyrimidin-4-yl) -5-methylcyclohexane-1,3-diamine (76b)

2,4-dichloro-5-fluoropyridine in a solution of 5-methylcyclohexane-1,3-diamine (76a) (2.2 g, 17.2 mmol) in isopropyl alcohol (40 mL) and acetonitrile (40 mL) Midine (1.4 g, 8.6 mmol) was added. The mixture was stirred at rt overnight, concentrated to dryness and purified on silica gel eluting with 1-20% methanol / dichloromethane to give racemic N ^1- (2-chloro-5-fluoropyrimidin-4-yl)- 0.6 g of 5-methylcyclohexane-1,3-diamine was obtained.

(3S) -N- (3-((2-chloro-5-fluoropyrimidin-4-yl) amino) -5-methylcyclohexyl) -3-fluoropyrrolidine-1-carboxamide ( Formation of 76c)

To a solution of N ^1- (2-chloro-5-fluoropyrimidin-4-yl) -5-methylcyclohexane-1,3-diamine (76b) (0.14 g. 0.54 mmol) in THF (2.5 mL) Carbonyldiimidazole (0.10 g, 0.60 mmol) and ⁱ Pr ₂ NEt (0.28 mL, 1.62 mmol) were added. The reaction was aged at room temperature for 2 hours and treated with (S) -3-fluoropyrrolidine hydrochloride (0.07 g, 0.54 mmol). The reaction was stirred at room temperature for 2 days, then concentrated to dryness, (3S) -N- (3-((2-chloro-5-fluoropyrimidin-4-yl) amino) -5 used without further purification. 202 mg of -methylcyclohexyl) -3-fluoropyrrolidine-1-carboxamide was obtained.

LCMS RT = 2.46 (M + 1) 374.2, (M-1) 372.

(3S) -3-fluoro-N- (3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) Formation of pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide (76d)

(3S) -N- (3-((2-chloro-5-fluoropyrimidin-4-yl) amino) -5-methyl-cyclohexyl) -3- in 2-methyltetrahydrofuran (4 mL) -3- To a solution of fluoropyrrolidine-1-carboxamide (XXc) (0.101 g, 0.270 mmol) potassium phosphate (0.090 g, 0.950 mmol), x-phos (0.027 g, 0.057 mmol) in water (1.2 mL) And Pd ₂ dba ₃ (0.015 g, 0.016 mmol). The reaction was heated to 120 ° C. for 20 minutes in a microwave, the organic phase was filtered through a pad of Florisil and the filtrate was concentrated in vacuo. The crude material was purified on silica gel eluting with EtOAc to give racemic (3S) -3-fluoro-N- (3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-blood). 127 mg of rolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide was obtained.

LCMS RT = 3.58 (M + l) 628.3, (M-1) 626.

(S) -3-fluoro-N-((1R, 3S, 5R) -3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine- 3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide (76e)

(3S) -3-fluoro-N- (3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] in MeOH (2.5 mL)) 25% methoxylation in methanol in a solution of pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide (76d) (0.090 g, 0.143 mmol) Sodium (2 mL) was added. The reaction was stirred at rt for 30 min and quenched with aqueous saturated NH ₄ Cl. Methanol was removed in vacuo and the residue was extracted with EtOAc and water. The organic phase was dried over sodium sulfate and concentrated to dryness. The crude racemate obtained was purified by SFC separation on chiral column. The second peak was concentrated in vacuo to give enantiomerically pure (S) -3-fluoro-N-((1R, 3S, 5R) -3-((5-fluoro-2- (5-fluoro-1H) 32 mg of -pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide was obtained as a white solid.

LCMS RT = 1.89 (M + 1) 474.2, (M-1) 472.4; SFC RT = 3.2 min, 15% MeOH, 5 mL / min, ODH (4.6 * 100), 100 bar, 35 C, 220 nm;

Scheme 77

(a) (R) -nopinone, O-methylhydroxylamine hydrochloride, pyridine, EtOH (b) nBuLi, THF, -78 ° C, ethylformate (c) NaBH ₄ , MeOH (d) TBDPSCl, imidazole , DMF (e) BH ₃ -THF, THF, 75 ° C. (f) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H- Pyrrolo [2,3-b] pyridine, ⁱ Pr ₂ NEt, 75 ° C. (g) HCl, dioxane

Formation of (1R, 5S) -6,6-dimethylbicyclo [3.1.1] heptan-2-one O-methyl oxime (77a)

O-methylhydroxylamine hydrochloride (2.05 g, 24.59 mmol) and pyridine in a solution of (1S, 5R) -6,6-dimethylnorfinan-2-one (3.09 g, 22.35 mmol) in ethanol (70 mL) (1.29 mL, 15.92 mmol) was added. The reaction mixture was heated to 80 ° C. for 4 hours. The solvent was removed under reduced pressure. The residue was diluted with 1N HCl and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated in vacuo to yield 3.36 g of a colorless oil (mixture of oxime isomers) used without further purification.

Formation of (1R, 3S, 5R) -2- (methoxyimino) -6,6-dimethylbicyclo [3.1.1] heptan-3-carbaldehyde (77b)

Cooling (-78 ° C) of (1R, 5S) -6,6-dimethylbicyclo [3.1.1] heptan-2-one O-methyl oxime (77a) (1.27 g, 7.59 mmol) in THF (33 mL) To the solution was added dropwise a solution of n-butyllithium (3.34 mL of 2.5M solution in hexane, 8.35 mmol). The mixture was stirred at −78 ° C. for 20 minutes, then ethyl formate (0.61 mL, 7.59 mmol) was added dropwise. The reaction mixture was stirred at −78 ° C. for 3 hours and then quenched by pouring into saturated aqueous NaHCO ₃ . The mixture was extracted with EtOAc. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (0-20% EtOAc / hexane gradient) to give 810 mg of yellow oil.

LCMS RT = 3.54 (M + H) 196.28.

Formation of (1R, 3S, 5R) -3- (hydroxymethyl) -6,6-dimethylbicyclo [3.1.1] heptan-2-one O-methyl oxime (77c)

(1R, 3S, 5R) -2- (methoxyimino) -6,6-dimethylbicyclo [3.1.1] heptan-3-carbaldehyde (77b) (0.70 g, 3.58 mmol) in methanol (15 mL) To the solution of was added sodium borohydride (0.16 g, 4.30 mmol). After stirring for 30 min at room temperature, the reaction was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (0-50% EtOAc / hexanes gradient) to give 330 mg of the desired alcohol as a mixture of oxime isomers.

(1R, 3S, 5R) -3-(((tert-butyldiphenylsilyl) oxy) methyl) -6,6-dimethyl-bicyclo [3.1.1] heptan-2-one O-methyl oxime (77d Formation of

(1R, 3S, 5R) -3- (hydroxymethyl) -6,6-dimethylbicyclo [3.1.1] -heptan-2-one O-methyl oxime (77c) (0.32 g) in DMF (6 mL) Tert-butylchlorodiphenylsilane (0.55 g, 2.00 mmol) and imidazole (0.22 g, 3.20 mmol) were added to the solution. The reaction mixture was stirred at rt for 18 h. The reaction was diluted with saturated aqueous NH ₄ Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue obtained was purified via silica gel chromatography (0-15% EtOAc / hexane gradient) to yield 200 mg of one oxime isomer and 197 mg of the second oxime isomer.

Formation of (1R, 3S, 5R) -3-(((tert-butyldiphenylsilyl) oxy) methyl) -6,6-dimethyl-bicyclo [3.1.1] heptan-2-amine (77e)

(1R, 3S, 5R) -3-(((tert-butyldiphenylsilyl) oxy) methyl) -6,6-dimethyl-bicyclo [3.1.1] heptan-2-one in THF (3 mL) To a solution of O-methyl oxime (77d) (0.20 g, 0.46 mmol) was added borane-THF (1.38 mL of 1 M solution, 1.38 mmol). The reaction was heated to 75 ° C. for 18 hours. The mixture was diluted with 1N NaOH (50 mL) and extracted twice with EtOAc. The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 178 mg of a colorless oil which was used without further purification.

LCMS RT = 2.53 (M + H) 408.54.

N-((1R, 2S, 3S, 5R) -3-(((tert-butyldiphenylsilyl) oxy) methyl) -6,6-dimethylbicyclo [3.1.1] heptan-2-yl)- Formation of 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine (77f)

(1R, 3S, 5R) -3-(((tert-butyldiphenylsilyl) oxy) methyl) -6,6-dimethyl-bicyclo [3.1.1] heptan-2-amine in DMF (1.5 mL) (77e) (0.20 g, 0.46 mmol) and 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3 diisopropylethylamine (0.11 mL, 0.61 mmol) was added to a solution of pyridine (0.14 g, 0.30 mmol). The reaction was heated to 75 ° C. for 18 hours. The mixture was diluted with saturated aqueous NH ₄ Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-5% MeOH / CH ₂ Cl ₂ gradient) to afford 78 mg of the desired product.

((1R, 2S, 3S, 5R) -2-((2- (5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-yl Formation of Amino) -6,6-dimethylbicyclo [3.1.1] heptan-3-yl) methanol (1229)

N-((1R, 2S, 3S, 5R) -3-(((tert-butyldiphenylsilyl) oxy) methyl) -6,6-dimethylbicyclo [3.1.1] in acetonitrile (1.1 mL) Heptan-2-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-fluoropyrimidin-4-amine (77f) ( To a solution of 0.037 g, 0.046 mmol) was added HCl (0.221 mL of 4M solution in dioxane, 0.883 mmol). The mixture was heated to 70 ° C. for 18 hours during which a precipitate formed. The reaction was concentrated in vacuo and triturated three times with CH ₃ CN to afford 4 mg of the desired product as a white solid.

Influenza Antiviral Assay

Antiviral assays were performed using two cell-based methods:

The 384-well microtiter plate modification of the standard cytopathic effect (CPE) assay is described in Noah, et al., Antiviral Res. 73: 50-60, 2006]. Briefly, MDCK cells were incubated at 37 ° C. for 72 hours at low multiplicity of infection (approximately MOI = 0.005) with test compounds and influenza A virus (A / PR / 8/34), and cell viability was ATP It was measured using detection (CellTiter Glo, Promega Inc.). Control wells containing cells and virus showed cell death, while wells containing cells, virus and active antiviral compounds showed cell survival (cell protection). Different concentrations of test compounds were evaluated four times, for example, over a range of approximately 20 μM to 1 nM. Dose-response curves were constructed using standard four-parameter curve matching and the concentration of test compound that induced 50% cell protection, or cell survival equivalent to 50% of uninfected wells, was reported as IC ₅₀ .

A second cell-based antiviral assay, which relies on the proliferation of virus-specific RNA molecules in infected cells, was run and a branched chain DNA (bDNA) hybridization method [Wagaman et al, J. Virol Meth, 105: 105] -114, 2002] to measure RNA levels directly. In this assay, cells are first infected in the wells of a 96-well microtiter plate, allowing the virus to replicate within the infected cells and spread to additional cells around, then lyse the cells and measure the viral RNA content. This assay is stopped early compared to the CPE assay, usually after 18 to 36 hours, but all target cells are still viable. Viral RNA, according to the kit manufacturer's instructions (Quantigene 1.0, Panomics, Inc.), hybridizes well lysates to specific oligonucleotide probes immobilized in the wells of the assay plate and then further linked to the reporter enzyme. It is quantified by amplifying the signal by hybridization with probes. Minus-strand viral RNA is measured using probes designed for the consensus type A hemagglutinin gene. Control wells containing cells and virus were used to define 100% viral replication levels and dose-response curves for antiviral test compounds were analyzed using 4-parameter curve matching. The concentration of test compound that induces viral RNA levels equivalent to 50% of control wells was reported as EC ₅₀ .

Virus and Cell Culture: Madin-David Dog Kidney Cells (CCL-34 American Type Culture Collection) were enriched with 2 mM L-glutamine, 1,000 U / ml penicillin, 1,000 μg / ml streptomycin, 10 mM HEPES and 10% fetal medium It was maintained in Dulbecco's Modified Eagle Medium (DMEM). For the CPE assay, the day before the assay, cells were suspended by trypsin treatment and 10,000 cells per well were dispensed into wells of 384 well plates in 50 μl. On assay day, adherent cells were washed three times with DMEM containing 1 μg / ml TPCK-treated trypsin without fetal bovine serum. The assay was initiated by adding 30 TCID ₅₀ of virus and test compound to a final volume of 50 μl in a medium containing 1 μg / ml TPCK-treated trypsin. Plates were incubated at 37 ° C. for 72 hours in a humidified 5% CO ₂ atmosphere. Alternatively, cells were grown as described above in DMEM + fetal bovine serum, but they were trypsinized on the day of assay, washed twice and suspended in serum-free EX-cell MDCK cell medium (SAFC Biosciences, Lenexa, KS). And plated in wells at 20,000 cells per well. These wells were then incubated for 5 hours and then used for the assay without the need for washing.

Influenza virus, strain A / PR / 8/34 (adapted to tissue culture) was obtained from ATCC (VR-1469). Low-passage virus stocks were prepared using standard methods (WHO Manual on Animal Influenza Diagnosis and Surveillance, 2002) among MDCK cells and tested by serial dilution on MDCK cells in the 384-well CPE assay format. TCID ₅₀ measurements were performed by calculating the results using the Karber method.

Average IC ₅₀ values (overall averages) for some specific compounds are summarized in Tables 1-5:

A: IC ₅₀ (overall mean) <5 μΜ;

B 5 μM ≦ IC ₅₀ (overall average) ≦ 20 μM;

C IC ₅₀ (overall average)> 10 μM;

D IC ₅₀ (overall average)> 20 μM;

E IC ₅₀ (overall average)> 3.3 μM.

Average EC ₅₀ values (overall averages) for some compounds are also summarized in Tables 1-5:

A: EC ₅₀ (overall mean) <5 μΜ;

B 5 μM ≦ EC ₅₀ (overall average) ≦ 10 μM;

C EC ₅₀ (overall average)> 3.3 μM;

D EC ₅₀ (overall average)> 10 μΜ.

As can be seen from Tables 1 to 5, many of the compounds of the present invention have a positive effect on the survival of A / PR / 8/34 infected cells and an inhibitory effect on the replication of A / PR / 8/34 influenza virus. Indicated. Exemplary IC ₅₀ and EC ₅₀ meanings are as follows: Compound 428 has an IC ₅₀ of 0.03 μM; Compound 895 has an IC ₅₀ of 0.0008 μM and an EC _{50 of} 0.001 μM; Compound 833 had an IC ₅₀ of 5.6 μM and an EC ₅₀ of 3.5 μM.

In vivo assay

For efficacy studies, Balb / c mice (4-5 weeks old) were inoculated at a total volume of 50 μl by intranasal drop (25 μl / nostril) with 5 × 10 ³ TCID ₅₀ under general anesthesia (ketamine / xylazine). Uninfected controls were inoculated in tissue culture medium (DMEM, 50 μl total volume). For the prophylactic study (FIG. 1), the initial dose of Compound 514 (100 mg / kg) or vehicle alone (0.5% methylcellulose / 0.5% Tween 80) was administered by oral gavage (10 ml / kg) 2 hours prior to infection. Administration was continued twice a day for 5 days. For therapeutic studies (FIG. 2), Compound 588 (200 mg / kg) or vehicle alone (0.5% methylcellulose / 0.5% Tween 80) is administered by oral gavage 24 hours after infection and twice daily for 10 days. Continued. Animals were monitored for survival for 21 days and Kaplan Meier plots were made. As shown in FIGS. 1 and 2, Compound 514 and Compound 588 provided statistically significant complete survival from vehicle treated controls (P <0.0001).

All documents provided herein are hereby incorporated by reference in their entirety. All abbreviations, symbols, and conventions used herein are described in contemporary scientific literature by Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors , 2nd Ed., Washington, DC: American Chemical Society , 1997].

While the invention has been described in connection with the detailed description thereof, it is to be understood that the foregoing description is for purposes of illustration only and is not intended to limit the scope of the invention, which is defined in the appended claims. Other aspects, advantages and modifications fall within the scope of the following claims.

Claims (156)

A compound of formula (IA) or a pharmaceutically acceptable salt thereof.
Formula IA

In Chemical Formula IA,
Z ¹ is -F, -Cl, or -H;
Z ² is -H;
Z ³ is -H;
R ¹ is -H;
R ² is -H;
R ³ is -H, -Cl, or -F;
R ⁴ is

ego; here,
Ring G3 and ring G4 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^A ;
Ring G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more J ^B ;
X is -NR ^g- ;
Q ² is independently a bond, -O-, -S-, -NR-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C (O ) NR-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR-, -NRCO _2- , -OC (O) NR—, —S (O) —, —SO ₂ —, —N (R) SO ₂ —, —SO ₂ NR′—, —NRSO ₂ NR′—, or — (CR ⁶ R ⁷ ) _p -Y ^1- ;
J ^A and J ^B are each independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q ¹ -R ⁵ , or, optionally, two J ^A or two J ^B are each independently attached Together with the atom (s) formed, form a 4-8 membered ring optionally substituted with one or more J ^El ;
Q ¹ is independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -S (O) -, -SO 2 -, -SO 2 NR'-, -NRSO 2 -, -NRSO 2 NR'-, or - (CR ⁶ R ⁷⁾ _p -Y ^1- ;
Y ¹ is independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -S (O)-, -SO _2- , -SO ₂ NR'-, -NRSO _2- , or -NRSO ₂ NR'-;
R ⁵ is i) -H; ii) a C ₁ -C ₆ aliphatic group optionally substituted with one or more J ^C1 ; Or iii) each independently is a C ₃ -C ₁₀ non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, optionally substituted with one or more J ^C1 ; Or iv) each independently a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, optionally substituted with one or more J ^D1 ;
R ⁶ and R ⁷ are each independently -H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ amino C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy, or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl;
R ⁸ and R ⁹ are each -H;
R ¹³ and R ¹⁴ are each independently —H, halogen, or substituents halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy ego;
R ²¹ , R ²² , R ²³ , R ²⁴ , and R ²⁵ are each -H;
R ^g is —H, or a substituent halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy;
R and R 'are each independently -H or substituents halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy;
Optionally, R ′ together with R ⁵ and the nitrogen atom to which they are attached form a 5-7 membered non-aromatic heterocycle optionally substituted with one or more J ^D1 ;
J ^C1 and J ^D1 are each independently halogen, cyano, oxo, R ^a , -OR ^b , -SR ^b , -S (O) R ^a , -SO ₂ R ^a , -NR ^b R ^c , -C ( O) R ^b , -C (= NR) R ^c , -C (= NR) NR ^b R ^c , -NRC (= NR) NR ^b R ^c , -C (O) OR ^b , -OC (O) R ^b , -NRC (O) R ^b , -C (O) NR ^b R ^c , -NRC (O) NR ^b R ^c , -NRC (O) OR ^b , -OCONR ^b R ^c , -C (O) NRCO ₂ R ^b , -NRC (O) NRC (O) OR ^b , -C (O) NR (OR ^b ), -SO ₂ NR ^c R ^b , -NRSO ₂ R ^b , -NRSO ₂ NR ^c R ^b ,- P (O) (OR ^a ) ₂ , -OP (O) (OR ^a ) ₂ , -P (O) ₂ OR ^a , and -CO ₂ SO ₂ R ^b or optionally 2 J ^C1 and two J ^D1 each independently form, together with the atom (s) to which they are attached, a 4-8 membered ring optionally substituted with one or more J ^E1 ;
J ^E1 are each independently halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl), and —C (O) (C ₁ -C ₆ -alkyl), wherein the alkyl groups are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ Optionally substituted with one or more substituents independently selected from the group consisting of -C ₄ alkoxy;
R ^a is independently:
i) halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O (C ₁ -C ₆ alkyl), -C (O) (C ₁ -C ₆ -alkyl), C ₃ -C ₈ C ₁ optionally substituted with one or more substituents independently selected from the group consisting of non-aromatic carbocycles, 4-8 membered non-aromatic heterocycles, 5-10 membered heteroaryl groups, and 6-10 membered carbocyclic aryl groups -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl group, wherein said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C represented by R ^a The alkyl groups for the substituents of the ₆ alkynyl groups are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy Optionally substituted with one or more substituents independently selected from the group consisting of; R ^a said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl represented by, or C ₂ -C ₆ alkynyl wherein the carbocycle for the substituents of the carbonyl groups, cyclic heterocycle, heteroaryl, and aryl carbonyl groups Are each independently optionally substituted with one or more J ^El ;
ii) each independently C ₃ -C ₈ non-aromatic carbocycle, or 4-8 membered non-aromatic heterocycle, optionally substituted with one or more J ^El ; or
iii) each independently a 5-10 membered heteroaryl, or a 6-10 membered carbocyclic aryl group, optionally substituted with one or more J ^El ;
R ^b and R ^c are each independently R ^a or -H; Optionally, R ^b and R ^c together with the nitrogen atom (s) to which they are attached form a 5-7 membered non-aromatic heterocycle optionally substituted with one or more J ^El ;
p is 1, 2, 3, or 4;
q is 0, 1, or 2;
x is 0, 1, or 2;
r is 1 or 2. The compound of claim 1, wherein Q ² is independently —O—, —CO ₂ —, —OC (O) —, —C (O) NR—, —NRC (O) —, —NRC (O) NR—, -NRCO _2- , -OC (O) NR-, -SO _2- , or-(CR ⁶ R ⁷ ) _p -Y ^1- . The compound of claim 2, wherein Q ² is independently —O— or —CO ₂ —. delete delete delete The compound of claim 1, wherein R ³ is —Cl or —F. delete delete The method of claim 1,
R ⁶ and R ⁷ are each independently —H or —CH ₃ or together with the carbon atom to which they are attached form a cyclopropane ring;
R ¹³ and R ¹⁴ are each independently —H or —CH ₃ . The compound of claim 1, wherein ring G3 to ring G5 are each independently halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, —NH ₂ , —NH (C ₁ -C ₆ alkyl), —N (C ₁ -C ₆ alkyl) ₂ , -O (C ₁ -C ₆ alkyl), -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C (O) N (C ₁ -C ₆ alkyl) ₂ , -C (O) (C ₁ -C ₆ -alkyl), -OC (O) (C ₁ -C ₆ alkyl), -NHC (O) (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) C (O) (C ₁ -C ₆ alkyl), and -CO ₂ R ^b optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ R ^b ; Wherein the alkyl groups are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ Independently from the group consisting of -C ₄ alkyl), -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy Optionally substituted with one or more substituents selected. The compound of claim 11, wherein ring G3 to ring G5 are each independently halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , Independent from the group consisting of -OC (O) (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ -alkyl), -CO ₂ H, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ alkyl Optionally substituted with one or more substituents selected from: wherein the alkyl groups are each independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -O (C ₁ -C ₄ alkyl) Compound. A pharmaceutical composition for reducing influenza virus in a patient, comprising a compound according to any one of claims 1 to 3, 7 and 10 to 12 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating influenza in a patient comprising a compound according to any one of claims 1 to 3, 7 and 10 to 12 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for inhibiting influenza virus replication in a patient comprising a compound according to any one of claims 1 to 3, 7 and 10 to 12 or a pharmaceutically acceptable salt thereof. A compound of formula II or a pharmaceutically acceptable salt thereof.
Formula II

In Chemical Formula II,
Z ¹ is -F;
Z ² is -H or C ₁ -C ₆ alkyl;
R ³ is —H, —F, —Cl, —CF ₃ , —NH ₂ , —NH (CH ₃ ), or —N (CH ₃ ) ₂ ;
Group-[C (R ¹³ R ¹⁴ )] _x -ring A -Q ² -R ⁵ are independently

Is selected from;
R ⁵ is independently
i) -H;
ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), C optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, C ₃ -C ₈ non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl ₁ -C ₆ -aliphatic group; or
iii) each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ Alkyl), and C ₅ -C ₆ non-aromatic carbocycle, 4-7 membered non-aromatic heterocycle, phenyl group, optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, or 5- 6-membered heteroaryl ring;
Wherein the alkyl groups for the substituents of R ⁵ are each independently halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy Optionally substituted with one or more substituents independently selected from the group;
The carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the C ₁ -C ₆ -aliphatic groups represented by R ⁵ are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl , -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), Optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy;
Ring A is halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl) optionally further substituted with one or more substituents independently selected from the group consisting of: wherein the alkyl groups are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ Alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy;
n is 1;
x is 0 or 1;
R ¹³ and R ¹⁴ are each -H;
only,
Ring A21 and ring A26 wherein Q ² -R ⁵ is -OR ⁵ or -NHR ⁵ are further substituted with one or more substituents other than -H. The method of claim 16,
Z ² is -H;
R ³ is -H, -F, or -Cl. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the formula: XIA or XIB.
Chemical Formula XIA

Formula XIB

In the above formulas XIA and XIB
Ring A is halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -N (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C _1- C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, is substituted with -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl), optionally added with one or more substituents independently selected from the group consisting of. The compound of claim 16, wherein x is zero. A pharmaceutical composition for reducing influenza virus in a patient, comprising the compound according to any one of claims 16 to 19 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating influenza in a patient comprising a compound according to any one of claims 16 to 19 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for inhibiting influenza virus replication in a patient, comprising the compound according to any one of claims 16 to 19 or a pharmaceutically acceptable salt thereof. A compound of formula III: or a pharmaceutically acceptable salt thereof.
Formula III

In Chemical Formula III,
Ring B is independently

Wherein Ring B is optionally independently substituted;
Q ³ are each independently -C (O)-, -CO _2- , -C (O) NR'-, -SO _{2- ,} -SO ₂ NR'-, -C (O) NRC (O) O- Or-(CR ⁶ R ⁷ ) _p -Y ^1- ;
Z ¹ is —H, —F, —Cl, —CH ₃ , —C (O) OCH ₃ , —CF ₃ , —OCH ₃ , or —CN;
Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), or -N (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;
R ³ is —H, —Cl, —F, —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —N (CH ₃ ) ₂ , or —OCH ₃ ;
R ⁵ is independently
i) -H;
ii) halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ alkyl), C optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, C ₃ -C ₈ non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl ₁ -C ₆ -aliphatic group; or
iii) each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -O (C ₁ -C ₄ alkyl), -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -OC (O) (C ₁ -C ₄ alkyl), -C (O) O (C ₁ -C ₄ Alkyl), and C ₃ -C ₇ non-aromatic carbocycle, 4-7 membered non-aromatic heterocycle, phenyl group, optionally substituted with one or more substituents independently selected from the group consisting of -CO ₂ H, or 5- 6-membered heteroaryl ring;
Wherein the alkyl groups for the substituents of R ⁵ are each independently halogen, cyano, hydroxy, oxo, —NH ₂ , —NH (C ₁ -C ₄ alkyl), —N (C ₁ -C ₄ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy Optionally substituted with one or more substituents independently selected from the group;
R ⁶ and R ⁷ are each independently -H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ amino C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy, or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl;
R ¹³ and R ¹⁴ are each independently —H, halogen, or substituents halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy Or, optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl;
R and R 'are each independently -H or C ₁ -C ₆ alkyl;
Y ¹ is independently a bond, -O-, -S-, -NR'-, -C (O)-, -C (= NR)-, -CO _2- , -OC (O)-, -C ( O) NR'-, -C (O) NRC (O) O-, -NRC (O) NRC (O) O-, -NRC (O)-, -NRC (O) NR'-, -NRCO _2- , -OC (O) NR'-, -S (O)-, -SO ₂ -,-SO ₂ NR'-, -NRSO _2- , or -NRSO ₂ NR'-;
p is 1, 2, 3, or 4;
m is 0, 1, or 2;
y is 0 or 1;
only,
When Q ³ is -C (O)-, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Optionally substituted phenyl group; Or an optionally substituted 5-6 membered heteroaryl group;
When Y ¹ is a bond, R ⁵ is a substituted C ₁ -C ₆ aliphatic group; Optionally substituted C ₃ -C ₇ non-aromatic carbocycles; Optionally substituted phenyl group; Or an optionally substituted 5-6 membered heteroaryl group. delete The compound of claim 23, wherein R ³ is —H, —Cl, or —F. The method of claim 23,
Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ , or -CN;
Halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl, wherein Z ² is -H or a substituent ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy A C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of. The method of claim 26,
Z ¹ is -H, -F, or -CN;
Halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl, wherein Z ² is -H or a substituent ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy A C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of. The compound of claim 23, wherein R ¹³ and R ¹⁴ are each independently substituted with one or more substituents independently selected from the group consisting of —H, halogen, or substituents halogen, hydroxy, and C ₁ -C ₆ alkoxy. ₁ -C ₆ alkyl. The compound of claim 28, wherein R ¹³ and R ¹⁴ are each independently —H or C ₁ -C ₄ alkyl. The compound of claim 23, wherein R ⁶ and R ⁷ are each independently —H or —CH ₃ or together with the carbon atom to which they are attached form a cyclopropane ring. The compound or pharmaceutically acceptable salt thereof according to claim 23, wherein the compound is represented by Formula XIIA or XIIB.
Formula XIIA

Formula XIIB

The compound of claim 23, wherein m is zero. The compound of claim 23, wherein the group-[C (R ¹³ R ¹⁴ )] _x -ring B -Q ³ -R ⁵ is

Having the structure wherein ring B2 is independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C _1- C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ -C ₂ Optionally further substituted with one or more substituents independently selected from the group consisting of haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H, and —CO ₂ (C ₁ -C ₄ alkyl). 34. A pharmaceutical composition for reducing influenza virus in a patient, comprising the compound according to any one of claims 23 and 25 to 33 or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition for treating influenza in a patient comprising a compound according to any one of claims 23 and 25 to 33 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for inhibiting influenza virus replication in a patient, comprising a compound according to any one of claims 23 and 25 to 33 or a pharmaceutically acceptable salt thereof. A compound of formula IV: or a pharmaceutically acceptable salt thereof.
Formula IV

In Formula IV,
Ring C is independently

Wherein ring C1 to ring C5 are each independently halogen, cyano, hydroxy, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C _1- C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl) Optionally substituted with one or more substituents independently selected from the group, wherein each alkyl group is independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ Optionally substituted with one or more substituents independently selected from the group consisting of -C ₄ alkoxy;
Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ , -OCH ₃ , or -CN;
Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), or -N (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;
R ³ is —H, —Cl, —F, —CN, —CF ₃ , —OCH ₃ , —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl), or —N (C ₁ -C ₄ Alkyl) ₂ ;
R ¹⁰ is independently —H, or a substituent halogen, cyano, hydroxy, oxo, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, C ₂ -C ₆ alkoxyalkoxy, C ₃ -C ₈ non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5- A C ₁ -C ₆ alkyl group optionally substituted with one or more substituents independently selected from the group consisting of six-membered heteroaryl groups; Wherein the carbocycle, phenyl, heterocycle, and heteroaryl groups for the substituents of the C ₁ -C ₆ alkyl group represented by R ¹⁰ are each independently halogen, cyano, hydroxy, oxo, amino, carboxy , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ cyanoalkyl, C ₂ -C ₆ alkoxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hydroxyalkyl, With C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy Optionally substituted with one or more substituents independently selected from the group consisting of: delete The compound of claim 37, wherein R ³ is —H, —Cl, or —F. The method of claim 37,
Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ , or -CN;
Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy A C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of. The method of claim 40,
Z ¹ is -H, -F, or -CN;
Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy A C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of. 38. The compound of claim 37, wherein R ¹⁰ is independently —H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ -alkoxyalkyl, C ₁ -C ₆ hydroxyalkyl, C _1- C ₆ aminoalkyl, or C ₁ -C ₆ cyanoalkyl. 43. The compound of claim 42, wherein R ¹⁰ is -H, or a substituent, halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) Optionally substituted with one or more substituents independently selected from the group consisting of ₂ , —OCO (C ₁ -C ₄ alkyl), —CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy C ₁ -C ₆ -alkyl. The compound of claim 43, wherein R ¹⁰ is —H or C ₁ -C ₆ -alkyl. 38. The compound of claim 37, wherein ring C1 to ring C5 are each independently halogen, cyano, hydroxy, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, C ₁ Optionally further substituted with one or more substituents independently selected from the group consisting of -C ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl). The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula XIII.
Formula XIII

47. A pharmaceutical composition for reducing influenza virus in a patient, comprising the compound according to any one of claims 37 and 39-46 or a pharmaceutically acceptable salt thereof. 47. A pharmaceutical composition for treating influenza in a patient comprising a compound according to any one of claims 37 and 39-46 or a pharmaceutically acceptable salt thereof. 47. A pharmaceutical composition for inhibiting influenza virus replication in a patient, comprising a compound according to any one of claims 37 and 39-46 or a pharmaceutically acceptable salt thereof. A compound of formula (V) or a pharmaceutically acceptable salt thereof.
Formula V

In Formula V,
Ring D is independently

Wherein ring D1 to ring D7 are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, —O (C ₁ -C ₄ alkyl), —NH ₂ , —NH (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) ₂ , -C (O) (C ₁ -C ₄ alkyl), -CO ₂ H, and -CO ₂ (C ₁ -C ₄ alkyl) Optionally substituted with one or more substituents independently selected from the group consisting of: wherein each alkyl group is independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and Optionally substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₄ alkoxy;
Each R ^d is independently —H, C ₁ -C ₆ alkyl, or —C (O) (C ₁ -C ₆ alkyl), wherein the alkyl moieties are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl),- Optionally substituted with one or more groups selected from CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy;
Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ , -OCH ₃ , or -CN;
Z ² is -H, C ₁ -C ₆ alkyl, -O (C ₁ -C ₆ alkyl), -NH ₂ , -NH (C ₁ -C ₆ alkyl), or -N (C ₁ -C ₆ alkyl) ₂ , wherein the alkyl groups are each independently halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy;
R ³ is —H, —Cl, —F, —CN, —CF ₃ , —OCH ₃ , —OH, —NH ₂ , —NH (C ₁ -C ₄ alkyl), or —N (C ₁ -C ₄ Alkyl) ₂ ;
R ¹³ and R ¹⁴ are each independently —H, halogen, or substituents halogen, cyano, oxo, hydroxy, amino, carboxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of ₆ aminoalkoxy, C ₁ -C ₆ cyanoalkoxy, C ₁ -C ₆ hydroxyalkoxy, and C ₂ -C ₆ alkoxyalkoxy Or, optionally, R ¹³ and R ¹⁴ together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl;
z is 1 or 2. delete 51. The compound of claim 50, wherein R ³ is -H, -Cl, or -F. 51. The method of claim 50,
Z ¹ is -H, -F, -Cl, -CF ₃ , -CH ₃ , or -CN;
Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy A C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of. The method of claim 53,
Z ¹ is -H, -F, or -CN;
Z ² is -H or a substituent halogen, cyano, hydroxy, oxo, C ₁ -C ₄ alkyl, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl ) ₂ , -OCO (C ₁ -C ₄ alkyl), -CO (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkoxy A C ₁ -C ₆ alkyl optionally substituted with one or more substituents independently selected from the group consisting of. The compound of claim 50, wherein R ¹³ and R ¹⁴ are each independently C, optionally substituted with one or more substituents independently selected from the group consisting of -H, halogen, or substituents halogen, hydroxy, and C ₁ -C ₆ alkoxy. ₁ -C ₆ alkyl. The compound of claim 55, wherein R ¹³ and R ¹⁴ are each independently —H or C ₁ -C ₄ alkyl. delete 51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: XIV.
Formula XIV

59. The compound of claim 58, wherein z is one. 51. The compound of claim 50, wherein ring D1 to ring D7 are each independently halogen, cyano, hydroxy, oxo, -NH ₂ , -NH (C ₁ -C ₂ alkyl), -NH (C ₁ -C ₂ alkyl) ₂ , C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ hydroxyalkyl, C ₂ -C ₄ alkoxyalkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ hydroxyalkoxy, Optionally further substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₂ haloalkoxy, C ₂ -C ₄ alkoxyalkoxy, —CO ₂ H, and —CO ₂ (C ₁ -C ₄ alkyl), compound. 61. A pharmaceutical composition for reducing influenza virus in a patient, comprising the compound of any one of claims 50, 52-56, and 58-60, or a pharmaceutically acceptable salt thereof. 61. A pharmaceutical composition for treating influenza in a patient comprising the compound of any one of claims 50, 52-56, and 58-60, or a pharmaceutically acceptable salt thereof. 61. A pharmaceutical composition for inhibiting influenza virus replication in a patient, comprising the compound of any one of claims 50, 52-56, and 58-60, or a pharmaceutically acceptable salt thereof. A compound selected from the following compound or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for reducing influenza virus in a patient, comprising the compound according to claim 64 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating influenza in a patient, comprising the compound according to claim 64 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for inhibiting influenza virus replication in a patient, comprising the compound according to claim 64 or a pharmaceutically acceptable salt thereof. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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